Process for synthesis of amino-methyl tetralin derivatives

ABSTRACT

Methods for producing a compound of formula k1 or k2 
     
       
         
         
             
             
         
       
     
     by reducing a dihydronapthalene amide compound of formula i 
     
       
         
         
             
             
         
       
     
     with hydrogen gas in the presence of a ruthenium catalyst of formula j1 or j2 
       Ru(Z) 2 (L)  j1; 
       Ru(E)(E′)(L)(D)  j2; 
     wherein m, n, Ar, Y, R 1  E, E′, D, Z and L are as defined herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is entitled to the benefit of U.S. ProvisionalApplication Ser. No. 61/138,596, filed Dec. 18, 2008, the disclosure ofwhich is incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to processes for making substituted indane andtetralin compounds that are useful for enhancing cognitive memory inpatients and for treating various central nervous system diseases.

BACKGROUND OF THE INVENTION

The actions of 5-hydroxytryptamine (5-HT) as a major modulatoryneurotransmitter in the brain are mediated through a number of receptorfamilies termed 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7.Based on a high level of 5-HT6 receptor mRNA in the brain, it has beenstated that the 5-HT6 receptor may play a role in the pathology andtreatment of central nerve system disorders. In particular,5-HT2-selective and 5-HT6 selective ligands have been identified aspotentially useful in the treatment of certain CNS disorders such asParkinson's disease, Huntington's disease, anxiety, depression, manicdepression, psychoses, epilepsy, obsessive compulsive disorders, mooddisorders, migraine, Alzheimer's disease (enhancement of cognitivememory), sleep disorders, feeding disorders such as anorexia, bulimiaand obesity, panic attacks, akathisia, attention deficit hyperactivitydisorder (ADHD), attention deficit disorder (ADD), withdrawal from drugabuse such as cocaine, ethanol, nicotine and benzodiazepines,schizophrenia, and also disorders associated with spinal trauma and/orhead injury such as hydrocephalus. Such compounds are also expected tobe of use in the treatment of certain gastrointestinal (GI) disorderssuch as functional bowel disorder. See for example, B. L. Roth et al.,J. Pharmacol. Exp. Ther., 1994, 268, pages 1403-14120, D. R. Sibley etal., Mol. Pharmacol., 1993, 43, 320-327, A. J. Sleight et al.,Neurotransmission, 1995, 11, 1-5, and A. J. Sleight et al., Serotonin IDResearch Alert, 1997, 2(3), 115-8.

While some 5-HT6 and 5-HT2A modulators are known, there continues to bea need for compounds that are useful for modulating the 5-HT6 receptor,the 5-HT2A receptor, or both.

SUMMARY OF THE INVENTION

The invention provides a method of producing a compound of formula k1 ork2

wherein:

-   -   m is 0 or 1;    -   n is from 0 to 3;    -   Ar is: aryl; or heteroaryl, each of which may be optionally        substituted with: halo;    -   C₁₋₆alkyl; C₁₋₆alkoxy; cyano; hydroxy; C₁₋₆alkylsulfonyl; or        halo-C₁₋₆alkyl;    -   Y is —O—; —S(O)_(p)— or —N—R^(a) wherein p is from 0 to 2 and        R^(a) is hydrogen or C₁₋₆alkyl; and    -   R¹ is: halo; C₁₋₆alkyl; C₁₋₆alkoxy; or halo-C₁₋₆alkyl;        the method comprising:    -   reducing a dihydronapthalene amide compound of formula i

with hydrogen gas in the presence of a Ruthenium catalyst of formula j1or j2

Ru(Z)₂(L)  j1;

Ru(E)(E′)(L)(D)  j2;

wherein:

D is an optionally chiral diamine;

E and E′ are both halo, or E is hydrogen and E′ is BH₄;

L is a chiral diphosphine ligand; and

Z is: halo or R^(b)—CO₂ ⁻ (carboxylate) wherein R^(b) is: C₁₋₆alkyl;halo-C₁₋₆alkyl; C₁₋₆alkoxy; aryl optionally substituted with halo; orheteroaryl optionally substituted with halo.

The method is useful for preparation of compounds that are effectivemodulators of the 5-HT₆ receptor. Also disclosed are compounds useful asintermediates in the methods of the invention.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise stated, the following terms used in this Application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an,” and “the” include pluralreferents unless the context clearly dictates otherwise.

“Alkyl” means the monovalent linear or branched saturated hydrocarbonmoiety, consisting solely of carbon and hydrogen atoms, having from oneto twelve carbon atoms. “Lower alkyl” refers to an alkyl group of one tosix carbon atoms, i.e. C₁-C₆alkyl. Examples of alkyl groups include, butare not limited to, methyl, ethyl, propyl, isopropyl, isobutyl,sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms, e.g., methylene, ethylene,2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene,and the like.

“Alkoxy” means a moiety of the formula —OR, wherein R is an alkyl moietyas defined herein. Examples of alkoxy moieties include, but are notlimited to, methoxy, ethoxy, isopropoxy, and the like.

“Alkoxyalkyl” means a moiety of the formula R^(a)—O—R^(b)—, where R^(a)is alkyl and R^(b) is alkylene as defined herein. Exemplary alkoxyalkylgroups include, by way of example, 2-methoxyethyl, 3-methoxypropyl,1-methyl-2-methoxyethyl, 1-(2-methoxyethyl)-3-methoxypropyl, and1-(2-methoxyethyl)-3-methoxypropyl.

“Alkylcarbonyl” means a moiety of the formula —C(O)—R′, where R′ isalkyl as defined herein. The term “Acyl may be used interchangeably with“Alkylcarbonyl”.

“Alkylsulfonyl” means a moiety of the formula —R′—R″, where R′ is —SO₂—and R″ is alkyl as defined herein.

“Alkylsulfonylalkyl means a moiety of the formula —R′—R″—R′″ where whereR′ is alkylene, R″ is —SO₂— and R′″ is alkyl as defined herein.

“Alkylamino means a moiety of the formula —NR—R′ wherein R is hydrogenor alkyl and R′ is alkyl as defined herein.

“Alkylsulfanyl” means a moiety of the formula —SR wherein R is alkyl asdefined herein.

“Aminoalkyl” means a group —R—R′ wherein R′ is amino and R is alkyleneas defined herein. “Aminoalkyl” includes aminomethyl, aminoethyl,1-aminopropyl, 2-aminopropyl, and the like. The amino moiety of“aminoalkyl” may be substituted once or twice with alkyl to provide“alkylaminoalkyl” and “dialkylaminoalkyl” respectively.“Alkylaminoalkyl” includes methylaminomethyl, methylaminoethyl,methylaminopropyl, ethylaminoethyl and the like. “Dialkylaminoalkyl”includes dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl,N-methyl-N-ethylaminoethyl, and the like.

“Aryl” means a monovalent cyclic aromatic hydrocarbon moiety consistingof a mono-, bi- or tricyclic aromatic ring. The aryl group can beoptionally substituted as defined herein. Examples of aryl moietiesinclude, but are not limited to, optionally substituted phenyl,naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl,oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl,diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl,benzodioxanyl, benzopyranyl, benzodioxylyl, benzopyranyl, benzoxazinyl,benzoxazinonyl, benzopiperadinyl, benzopiperazinyl, benzopyrrolidinyl,benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, and thelike, including partially hydrogenated derivatives thereof. Preferredaryl are phenyl and napthyl, and more preferably phenyl, which may beoptionally substituted as defined below.

“Arylalkyl” and “Aralkyl”, which may be used interchangeably, mean aradical-R^(a)R^(b) where R^(a) is an alkylene group and R^(b) is an arylgroup as defined herein; e.g., phenylalkyls such as benzyl, phenylethyl,3-(3-chlorophenyl)-2-methylpentyl, and the like are examples ofarylalkyl.

“Arylalkyl” means a group of the formula —R—R′ wherein R is alkylene andR′ is aryl as defined herein.

“Arylsulfonyl means a group of the formula —SO₂—R wherein R is aryl asdefined herein.

“Aryloxy” means a group of the formula —O—R wherein R is aryl as definedherein.

“Aralkyloxy” means a group of the formula —O—R—R″ wherein R is alkyleneand R′ is aryl as defined herein.

“Cycloalkyl” means a monovalent saturated carbocyclic moiety consistingof mono- or bicyclic rings. Cycloalkyl can optionally be substitutedwith one or more substituents, wherein each substituent is independentlyhydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, ordialkylamino, unless otherwise specifically indicated. Examples ofcycloalkyl moieties include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like,including partially unsaturated derivatives thereof.

“Cycloalkylalkyl” means a moiety of the formula —R′—R″, where R′ isalkylene and R″ is cycloalkyl as defined herein.

“Heteroalkyl” means an alkyl radical as defined herein wherein one, twoor three hydrogen atoms have been replaced with a substituentindependently selected from the group consisting of −OR^(a),—NR^(b)R^(c) and —S(O)_(n)R^(d) (where n is an integer from 0 to 2),with the understanding that the point of attachment of the heteroalkylradical is through a carbon atom, wherein R^(a) is hydrogen, acyl,alkyl, cycloalkyl, or cycloalkylalkyl; R^(b) and R^(c) are independentlyof each other hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; andwhen n is 0, R^(d) is hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl,and when n is 1 or 2, R^(d) is alkyl, cycloalkyl, cycloalkylalkyl,amino, acylamino, monoalkylamino, or dialkylamino. Representativeexamples include, but are not limited to, 2-hydroxyethyl,3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl,1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl,2-hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl,2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl, aminosulfonylpropyl, methylaminosulfonylmethyl, methylaminosulfonylethyl,methylaminosulfonylpropyl, and the like.

“Heteroaryl” means a monocyclic or bicyclic radical of 5 to 12 ringatoms having at least one aromatic ring containing one, two, or threering heteroatoms selected from N, O, or S, the remaining ring atomsbeing C, with the understanding that the attachment point of theheteroaryl radical will be on an aromatic ring. The heteroaryl ring maybe optionally substituted as defined herein. Examples of heteroarylmoieties include, but are not limited to, optionally substitutedimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl,pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl,isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl,benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl,benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl,triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl,naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyland the like, including partially hydrogenated derivatives thereof.

“Heteroarylalkyl” or “heteroaralkyl” means a group of the formula —R—R′wherein R is alkylene and R′ is heteroaryl as defined herein.

“Heteroaryloxy” means a group of the formula —O—R wherein R isheteroaryl as defined herein.

The terms “halo”, “halogen” and “halide”, which may be usedinterchangeably, refer to a substituent fluoro, chloro, bromo, or iodo.

“Haloalkyl” means alkyl as defined herein in which one or more hydrogenhas been replaced with same or different halogen. Exemplary haloalkylsinclude —CH₂Cl, —CH₂CF₃, —CH₂CCl₃, perfluoroalkyl (e.g., —CF₃), and thelike.

“Haloalkoxy” means a moiety of the formula —OR, wherein R is a haloalkylmoiety as defined herein. An exemplary haloalkoxy is difluoromethoxy.

“Heterocycloamino” means a saturated ring wherein at least one ring atomis N, NH or N-alkyl and the remaining ring atoms form an alkylene group.

“Heterocyclyl” means a monovalent saturated moiety, consisting of one tothree rings, incorporating one, two, or three or four heteroatoms(chosen from nitrogen, oxygen or sulfur). The heterocyclyl ring may beoptionally substituted as defined herein. Examples of heterocyclylmoieties include, but are not limited to, optionally substitutedpiperidinyl, piperazinyl, homopiperazinyl, azepinyl, pyrrolidinyl,pyrazolidinyl, imidazolinyl, imidazolidinyl, pyridinyl, pyridazinyl,pyrimidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl,isothiazolidinyl, quinuclidinyl, quinolinyl, isoquinolinyl,benzimidazolyl, thiadiazolylidinyl, benzothiazolidinyl,benzoazolylidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl,tetrahydropyranyl, thiamorpholinyl, thiamorpholinylsulfoxide,thiamorpholinylsulfone, dihydroquinolinyl, dihydrisoquinolinyl,tetrahydroquinolinyl, tetrahydrisoquinolinyl, and the like.

“Heterocyclylalkyl” means a moiety of the formula —R—R′ wherein R isalkylene and R′ is heterocyclyl as defined herein.

“Heterocyclyloxy” means a moiety of the formula —OR wherein R isheterocyclyl as defined herein.

“Heterocyclylalkoxy” means a moiety of the formula —OR—R′ wherein R isalkylene and R′ is heterocyclyl as defined herein.

“Hydroxyalkoxy” means a moiety of the formula —OR wherein R ishydroxyalkyl as defined herein.

“Hydroxyalkylamino” means a moiety of the formula —NR—R′ wherein R ishydrogen or alkyl and R′ is hydroxyalkyl as defined herein.

“Hydroxyalkylaminoalkyl” means a moiety of the formula —R—NR′—R″ whereinR is alkylene, R′ is hydrogen or alkyl, and R″ is hydroxyalkyl asdefined herein.

“Hydroxycarbonylalkyl” or “carboxyalkyl” means a group of the formula—R—(CO)—OH where R is alkylene as defined herein.

“Hydroxyalkyloxycarbonylalkyl” or “hydroxyalkoxycarbonylalkyl” means agroup of the formula —R—C(O)—O—R—OH wherein each R is alkylene and maybe the same or different.

“Hydroxyalkyl” means an alkyl moiety as defined herein, substituted withone or more, preferably one, two or three hydroxy groups, provided thatthe same carbon atom does not carry more than one hydroxy group.Representative examples include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl

“Hydroxycycloalkyl” means a cycloalkyl moiety as defined herein whereinone, two or three hydrogen atoms in the cycloalkyl radical have beenreplaced with a hydroxy substituent. Representative examples include,but are not limited to, 2-, 3-, or 4-hydroxycyclohexyl, and the like.

“Polar aprotic solvent” means a solvent comprised of molecules havingpolar groups thereon, but without mobile protons. Exemplary polaraprotic solvents include, without limitation, dimethyl formamide,acetonitrile, dimethyl sulfoxide, N,N-dimethyl acetamide,N-methylpyrrolidinone, tetrahydrofuran, dioxane, ethyl acetate,tetrahydropyran, pyridine, acetone, 2-propanone, 2-butanone, ethyleneglycol dimethyl ether, methylene chloride, chloroform, and the like.

“Urea” or “ureido” means a group of the formula —NR′-C(O)—NR″R′″ whereinR′, R″ and R′″ each independently is hydrogen or alkyl.

“Carbamate” means a group of the formula —O—C(O)—NR′R″ wherein R′ and R″each independently is hydrogen or alkyl.

“Carboxy” means a group of the formula —O—C(O)—OH.

“Sulfonamido” means a group of the formula —SO₂—NR′R″ wherein R′, R″ andR′″ each independently is hydrogen or alkyl.

“Optionally substituted”, when used in association with “aryl”, phenyl”,“heteroaryl” “cycloalkyl”, “heterocyclyl”, or “aniline” means an aryl,phenyl, heteroaryl, cyclohexyl, heterocyclyl or aniline which isoptionally substituted independently with one to four substituents,preferably one or two substituents selected from alkyl, cycloalkyl,cycloalkylalkyl, heteroalkyl, hydroxyalkyl, halo, nitro, cyano, hydroxy,alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino, haloalkyl,haloalkoxy, heteroalkyl, —COR (where R is hydrogen, alkyl, phenyl orphenylalkyl), —(CR′R″)_(n)—COOR (where n is an integer from 0 to 5, R′and R″ are independently hydrogen or alkyl, and R is hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl), or—(CR′R″)_(n)—CONR^(a)R^(b) (where n is an integer from 0 to 5, R′ and R″are independently hydrogen or alkyl, and R^(a) and R^(b) are,independently of each other, hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, phenyl or phenylalkyl). Certain preferred optionalsubstituents for “aryl”, phenyl”, “heteroaryl” “cycloalkyl” or“heterocyclyl” include alkyl, halo, haloalkyl, alkoxy, cyano, amino andalkylsulfonyl. More preferred substituents are methyl, fluoro, chloro,trifluoromethyl, methoxy, amino and methanesulfonyl.

“Leaving group” means the group with the meaning conventionallyassociated with it in synthetic organic chemistry, i.e., an atom orgroup displaceable under substitution reaction conditions. Examples ofleaving groups include, but are not limited to, halogen, alkane- orarylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy,thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy,dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy,acyloxy, and the like. Preferred examples of a leaving group are halo,H₂N— or CH₃COO—. Particularly preferred are chloride, H₂N— or CH₃COO—.

“Modulator” means a molecule that interacts with a target. Theinteractions include, but are not limited to, agonist, antagonist, andthe like, as defined herein.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not.

“Disease” and “Disease state” means any disease, condition, symptom,disorder or indication.

“Inert organic solvent” or “inert solvent” means the solvent is inertunder the conditions of the reaction being described in conjunctiontherewith, including for example, benzene, toluene, acetonitrile,tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chlorideor dichloromethane, dichloroethane, diethyl ether, ethyl acetate,acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol,tert-butanol, dioxane, pyridine, and the like. Unless specified to thecontrary, the solvents used in the reactions of the present inventionare inert solvents.

“Protective group” or “protecting group” means the group whichselectively blocks one reactive site in a multifunctional compound suchthat a chemical reaction can be carried out selectively at anotherunprotected reactive site in the meaning conventionally associated withit in synthetic chemistry. Certain processes of this invention rely uponthe protective groups to block reactive nitrogen and/or oxygen atomspresent in the reactants. For example, the terms “amino-protectinggroup” and “nitrogen protecting group” are used interchangeably hereinand refer to those organic groups intended to protect the nitrogen atomagainst undesirable reactions during synthetic procedures. Exemplarynitrogen protecting groups include, but are not limited to,trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl(carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like. Theartisan in the art will know how to chose a group for the ease ofremoval and for the ability to withstand the following reactions.

“Solution” as used herein is meant to encompass liquids wherein areagent or reactant is present in a solvent in dissolved form (as asolute) or is present in particulate, undissolved form, or both. Thus,in a “solution”, it is contemplated that the solute may not be entirelydissolved therein and solid solute may be present in dispersion orslurry form. Accordingly, a “solution” of a particular reagent orreactant is meant to encompasses slurries and dispersions, as well assolutions, of such reagents or reactants. “Solution” and “Slurry” may beused interchangeable herein.

“Solvent” as used herein is meant to encompass liquids that fullydissolve a reagent or reactant exposed to the solvent, as well asliquids which only partially dissolve the reagent or reactant or whichact as dispersants for the reagent or reactant. Thus, when a particularreaction is carried out in a “solvent”, it is contemplated that some orall of the reagents or reactants present may not be in dissolved form.

“Solvates” means solvent additions forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrate. A solvate may comprise differingratios of number of molecules or moles of compound per molecule or moleof solvent present in the solvate. For example, a solvate may comprise a1:1 relationship (mono-solvate), a 2:1 relationship (hemi-solvate), a1:2 relationship (di-solvate, or the like, of compound to solvent.

“Subject” means mammals and non-mammals. Mammals means any member of themammalia class including, but not limited to, humans; non-human primatessuch as chimpanzees and other apes and monkey species; farm animals suchas cattle, horses, sheep, goats, and swine; domestic animals such asrabbits, dogs, and cats; laboratory animals including rodents, such asrats, mice, and guinea pigs; and the like. Examples of non-mammalsinclude, but are not limited to, birds, and the like. The term “subject”does not denote a particular age or sex.

“Therapeutically effective amount” means an amount of a compound that,when administered to a subject for treating a disease state, issufficient to effect such treatment for the disease state. The“therapeutically effective amount” will vary depending on the compound,disease state being treated, the severity or the disease treated, theage and relative health of the subject, the route and form ofadministration, the judgment of the attending medical or veterinarypractitioner, and other factors.

The terms “those defined above” and “those defined herein” whenreferring to a variable incorporates by reference the broad definitionof the variable as well as preferred, more preferred and most preferreddefinitions, if any.

“Treating” or “treatment” of a disease state includes:

-   -   (i) preventing the disease state, i.e. causing the clinical        symptoms of the disease state not to develop in a subject that        may be exposed to or predisposed to the disease state, but does        not yet experience or display symptoms of the disease state.    -   (ii) inhibiting the disease state, i.e., arresting the        development of the disease state or its clinical symptoms, or    -   (iii) relieving the disease state, i.e., causing temporary or        permanent regression of the disease state or its clinical        symptoms.

The terms “treating”, “contacting” and “reacting” when referring to achemical reaction means adding or mixing two or more reagents underappropriate conditions to produce the indicated and/or the desiredproduct. It should be appreciated that the reaction which produces theindicated and/or the desired product may not necessarily result directlyfrom the combination of two reagents which were initially added, i.e.,there may be one or more intermediates which are produced in the mixturewhich ultimately leads to the formation of the indicated and/or thedesired product.

Nomenclature and Structures

In general, the nomenclature used in this Application is based onAUTONOM™ v.4.0, a Beilstein Institute computerized system for thegeneration of IUPAC systematic nomenclature. Chemical structures shownherein were prepared using ISIS® version 2.2. Any open valency appearingon a carbon, oxygen or nitrogen atom in the structures herein indicatesthe presence of a hydrogen atom. Where a chiral center is present in astructure but no specific stereochemistry is shown, both stereoisomersassociated with the chiral center are encompassed by the structure.

Methods

U.S. patent application Ser. No. 11/315,706, filed on Dec. 21, 2005,published as US20060167255, and U.S. patent application Ser. No.11/280,712 filed on Jun. 20, 2007, published as US20080015256, thedisclosures of which are incorporated herein by reference, disclosecompounds effective as modulators of the 5-HT₆ and 5-HT2_(a) receptorsand uses of these compounds for treatment of CNS diseases. Thisinvention provides methods useful for preparing such compounds, andchemical intermediates useful in such methods.

The methods of the invention will be more fully understood by firstreferring to Scheme A below, wherein:

R is C₁₋₆alkyl and may be the same or different in each occurrence;

X is a leaving group and may be the same or different in eachoccurrence;

m is 0 or 1;

n is from 0 to 3;

Ar is: aryl; or heteroaryl, each of which may be optionally substitutedwith: halo; C₁₋₆alkyl; C₁₋₆alkoxy; cyano; hydroxy; C₁₋₆alkylsulfonyl; orhalo-C₁₋₆alkyl;

Y is —O—; —S(O)_(p)— or —N—R^(a) wherein p is from 0 to 2 and R^(a) ishydrogen or C₁₋₆alkyl;

D is an optionally chiral diamine;

E and E′ are both halo, or E is hydrogen and E′ is BH₄;

L is a chiral diphosphine ligand as described further below;

Z is: halo or R^(b)—CO₂ ⁻ (carboxylate) wherein R^(b) is: C₁₋₆alkyl;halo-C₁₋₆alkyl; C₁₋₆alkoxy; aryl optionally substituted with halo; orheteroaryl optionally substituted with halo;

R¹ is: halo; C₁₋₆alkyl; C₁₋₆alkoxy; or halo-C₁₋₆alkyl; and

R² is —C(O)—R^(c) or —SO₂—R^(c) wherein R^(c) is C₁₋₆alkyl or—NR^(d)R^(e) wherein R^(d) and R^(e) each independently is hydrogen orC₁₋₆alkyl.

In step 1 of scheme A, fluorophenyl compound a is reacted with an estercompound b, to afford phenyl-alkyl carboxylic ester compound c. Inembodiments where m=0, ester compound b is a propionate, and where m=1,compound b is a butyrate. R is preferably methyl or ethyl. Thealkylation reaction of step 1 may be carried out, for example, underpolar aprotic solvent conditions, such as in solution with NMP (N-methylpyrrolidinone). The reaction may be carried out in the presence of zincand iodine such that an intermediate zincate (not shown) compound isformed. The reaction may further be carried out in the presence of aphosphinylNi(II) catalyst such as bis(triphenylphosphine)Ni(II)chloride.

In step 2 the ester compound c undergoes hydrolysis to providephenyl-alkyl carboxylic acid compound d. This hydrolysis may be carriedout, for example, under aqueous conditions in the presence of base suchas NaOH to form the corresponding carboxylate (not shown), which maythen be treated with acid to give the corresponding carboxylic acid d.

A cyclization reaction is carried out in step 3 wherein compound dundergoes interal ring closure under aqueous acidic conditions to form acyclicy ketone compound e. The reaction of step 3 may in manyembodiments be effectively carried out in concentrated H₂SO₄. Where m=0,the cyclization of step 3 results in formation of an indane compound(not shown), and where m=1 results in formation of a tetralin compoundas shown.

In step 4, tetralone compound e is reacted with nucleophilic arylcompound f to yield aryl substituted tetralone g. Compound f maycomprise, for example, an aniline compound, a phenol compound or athiophenol compound. The reaction of step 4 may be carried out underpolar aprotic solvent conditions using NMP or a like solvent.

Cyclic ketone compound g is treated with cyanide in step 5 to givedihydronaphthalene carbonitrile compound h. The reaction of step 5 maybe carried out in a non-polar solvent such as toluene. Trimethylsilylcyanide (TMSCN) may be used as a cyanate source for step 5. Thisreaction may be carried out in the presence of AlCl₃. Carbonitrilecompound h need not be isolated in certain embodiments, and thuscompound h is shown in brackets.

In step 6, dihydronaphthalene carbonitrile compound h is hydrolyzed toform the corresponding dihydronaphthalene amide compound i. Thehydrolysis may be achieved using sulfuric acid under aqueous conditions.As noted above, in certain embodiments nitrile compound h need not beisolated, and the events of steps 5 and 6 may occur in the same reactionvessel.

In step 7, dihydronaphthalene amide compound i is reduced, using eitherof chiral ruthenium catalysts j1 or j2, in the presence of hydrogen gas,to afford tetralin amide compound k1 or k2, depending on theconfiguration of catalyst j1 or j2. Several chiral ruthenium catalystsj1, j2 may be used in this step and are described in detail below. Useof (S) enantiomer catalyst j1 or j2 in the reduction of step 7 resultsprimarily in (R) k1 as product, while use of (R) enantiomer catalyst j1or j2 results primarily in (S) k2. In many embodiments an (S) enantiomercatalyst j1 or j2 is used to produce (R) enantiomer product k1.

One preferred catalyst j1 for preparing (R) enantiomer k1 is[Ru(OAc)₂(S)3,3′-Diphenyl-6,6′-dimethoxybiphenyl-2,2′-diyl)-bis-diphenylphosphine],also known as [Ru(OAc)₂(S)-MeOBIPHEP)]. The reduction of step 7 may becarried out using a polar aprotic solvent such as tetrahydrofuran (THF).In certain embodiments amide compound k1 or k2 does not requireisolation, and step 8 may be carried out directly in the same reactionvessel used in step 6.

In step 8, a further reduction is carried out to convert chiral tetralinamide compound k1 or k2 to the corresponding chiral methylamino tetralincompound m1 or m2. The reduction of step 8 may be carried out, forexample, using borane in a polar aprotic solvent such as THF. Theconfiguration of compound k1 or k2 is preserved in the correspondingreduced product m1 or m2.

In step 9, aminomethyl tetralin compound m1 or m2 is treated withreagent n to afford tetralin compound o1 or o2. Reagent n may comprise,for example, an acyl halide such as acetyl chloride or otherC₁₋₆carboxylic acid chloride, a urea, an acyl anhydride such as aceticanhydride or other C₁₋₆carboxylic acid anhydride, or a sulfonyl halidesuch as methanesulfonyl chloride. The reaction of step 9 may be carriedout in solvents such as water or NMP. The configuration of compound m1or m2 is preserved in the product compound o1 or o2.

In embodiments of the invention wherein Y is sulfur, an optionaloxidation may be carried out in step 10 wherein compound o1 or o2 istreated with peracid, hydrogen peroxide, or like oxidizing agent toafford sulfonyl compound p1 or p2. The configuration of compound o1 oro2 is preserved in the product compound p1 or p2.

Accordingly, the invention provides a method of producing a tetralin orindan amide of formula k1 or k2

wherein:

-   -   m is 0 or 1;    -   n is from 0 to 3;    -   Ar is: aryl; or heteroaryl, each of which may be optionally        substituted with: halo;    -   C₁₋₆alkyl; C₁₋₆alkoxy; cyano; hydroxy; C₁₋₆alkylsulfonyl; or        halo-C₁₋₆alkyl;    -   Y is —O—; —S(O)_(p)— or —NR^(a)— wherein p is from 0 to 2 and        R^(a) is hydrogen or C₁₋₆alkyl; and    -   R¹ is: halo; C₁₋₆alkyl; C₁₋₆alkoxy; or halo-C₁₋₆alkyl;        the method comprising:

reducing a dihydronapthalene amide compound of formula i

with hydrogen gas in the presence of a Ruthenium catalyst of formula j1or j2

Ru(Z)₂(L)  j1

Ru(E)(E′)(L)(D)  j2

wherein:

D is an optionally chiral diamine;

E and E′ are both halo, or E is hydrogen and E′ is BH₄;

L is a chiral diphosphine ligand; and

Z is: halo or R^(b)—CO₂ ⁻ (carboxylate) wherein R^(b) is: C₁₋₆alkyl;halo-C₁₋₆alkyl; C₁₋₆alkoxy; aryl optionally substituted with halo; orheteroaryl optionally substituted with halo.

In certain embodiments of the invention, m is 1.

In certain embodiments, m is 0.

In certain embodiments, n is 0 or 1.

In certain embodiments, n is 0.

In certain embodiments, n is 1.

In certain embodiments, Ar is phenyl optionally substituted with: halo;C₁₋₆alkyl; C₁₋₆alkoxy; cyano; hydroxy; C₁₋₆alkylsulfonyl; orhalo-C₁₋₆alkyl.

In certain embodiments, Ar is phenyl optionally substituted with:fluoro; methyl; methoxy; cyano; hydroxy; methanesulfonyl; ortrifluoromethyl.

In certain embodiments, Ar is phenyl optionally substituted with fluoro.

In certain embodiments, Ar is: heteroaryl selected from: indolyl;pyrrolyl; pyrazolyl; imidazolyl; and benzimidazolyl, each optionallysubstituted with halo, preferably fluoro.

In certain embodiments, Ar is: heteroaryl selected from: indol-3-yl;5-fluoro-indol-3-yl; pyrrol-3-yl; 1-methyl-pyrrol-3-yl; pyrazol-4-yl;1-methyl-imidazol-2-yl; and 5-fluoro-benzimidazol-7-yl.

In certain embodiments, Y is S.

In certain embodiments, Z is acetate (CH₃COO⁻).

In certain embodiments, the catalyst is j1.

In certain embodiments, the catalyst is j2.

In certain embodiments, the chiral diphosphine L is selected from thegroup consisting of (R) or (S)-enantiomers of:

MeOBIPHEP;

(2-Furyl)-MeOBIPHEP)];

pTol-MeOBIPHEP;

3,5-Me,4-MeO-MeOBIPHEP;

3,5-iPr,4-MeO-MeOBIPHEP);

3,5-tBu-MeOBIPHEP;

3,5-tBu,4-MeO-MeOBIPHEP;

3,5-TMS-MeOBIPHEP;

TriMeOBIPHEP;

iPr-MeOBIPHEP;

Cy-MeOBIPHEP;

BenzoylOBIPHEP;

BITIANP;

BIPHEMP;

(2-Furyl)-BIPHEMP;

Et-Duphos;

BICP; and

PPF-P(tBu)2).

In certain embodiments, the chiral diphosphine ligand L is an (R) or(S)-enantiomer of:

MeOBIPHEP;

BIPHEMP;

TMBTP;

2-Naphthyl)-MeOBIPHEP;

(6-MeO-2-Naphthyl)-MeOBIPHEP;

2-(Thienyl)-MeOBIPHEP;

3,5-tBu-MeOBIPHEP;

PHANEPHOS;

BICP;

TriMeOBIPHEP;

(R,R,S,S)-Mandyphos;

BnOBIPHEP;

BenzoylBIPHEP;

pTol-BIPHEMP;

tButylCOOBIPHEP;

iPrOBIPHEP;

p-Phenyl-MeOBIPHEP;

pAn-MeOBIPHEP;

pTol-MeOBIPHEP;

3,5-Xyl-MeOBIPHEP;

3,5-Xyl-BIPHEMP;

BINAP;

2-Furyl-MeOBIPHEP;

3,5-Xyl-4-MeO-MeOBIPHEP;

2-Furyl-MeOBIPHEP; and

BITIANP.

In certain embodiments, the chiral diphosphine ligand L is an (R) or(S)-enantiomer of MeOBIPHEP.

In certain embodiments, the chiral diphosphine L is (S)-MeOBIPHEP.\

In certain embodiments, the chiral diphosphine L is (R)-MeOBIPHEP.

In certain embodiments, L is(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis-diphenylphosphine (MeOBIPHEP).

In certain embodiments D is 1,2-bis-diphenyl-ethylenediamine (DPEN).

In certain embodiments, L is (S)-3,5-Xyl-MeOBIPHEP.

In certain embodiments, the catalyst is [Ru(OAc)₂((S)-MeOBIPHEP)] or[Ru(OAc)₂((R)-MeOBIPHEP)].

In certain embodiments, the catalyst is [Ru(OAc)₂((S)-MeOBIPHEP)].

In certain embodiments, the catalyst is [Ru(OAc)₂((R)-MeOBIPHEP)].

In certain embodiments, catalyst j1 is[Ru(OAc)₂((S)-(6,6′-Dimethoxy-biphenyl-2,2′-diyl)bis(diphenylphosphine))]and the tetralin amide compound of formula k1 is produced.

In certain embodiments, catalyst j2 is[Ru(OAc)₂((S)-3,5-Xyl-MeOBIPHEP)((R,R)-DPEN)] and the tetralin amidecompound of formula k1 is produced.

The method of the invention further comprises:

reducing a compound of formula k1 or k2

to provide a compound of formula m1 or m2

wherein m, n, Y, Ar and R¹ are as defined herein.

In certain embodiments a compound of formula k1 is reduced to form acompound of formula m1.

In certain embodiments a compound of formula k2 is reduced to form acompound of formula m2.

In certain embodiments the reducing of the compound of formula k1 or k2is carried out using borane.

The method of the invention may further comprise:

reacting a compound of formula m1 or m2

with a reagent of formula n

X—R²  n;

to form a compound of formula o1 or o2

wherein:

-   -   X is a leaving group;    -   R² is: —C(O)—R^(c) or —SO₂—R^(c) wherein R^(c) is C₁₋₆alkyl or        —NR^(d)R^(e) wherein R^(d) and R^(e) each independently is        hydrogen or C₁₋₆alkyl; and m, n, Y, Ar and R¹ are as defined        herein.

In certain embodiments a compound of formula m1 is reacted with acompound of formula n to form a compound of formula o1.

In certain embodiments a compound of formula m2 is reacted with acompound of formula n to form a compound of formula o2.

In certain embodiments the leaving group X is halo.

In certain embodiments the compound of formula n is acetyl chloride.

In certain embodiments the compound of formula n is urea.

In certain embodiments the compound of formula n is acetic anhydride.

In certain embodiments the compound of formula n is methanesulfonylchloride.

The method may further comprise hydrolyzing/oxidizing adihydronaphthalene carbonitrile compound h

to form the compound of formula i

wherein m, n, Y, Ar and R¹ are as defined herein.

In other embodiments the method may comprise treating a compound offormula g

with cyanate, followed by treatment with sulfuric acid,to form the compound of formula i

wherein m, n, Y, Ar and R¹ are as defined herein.

The method may further comprise reacting a compound of formula g

with cyanate, to afford the compound of formula h

wherein m, n, Y, Ar and R¹ are as defined herein.

The method may further comprise reacting a compound of formula e

with a compound of formula f

Ar—YH  f;

to form the compound of formula g

wherein m, n, Y, Ar and R¹ are as defined herein.

The method may further comprise cyclizing a compound of formula d

to form the compound of formula e.

wherein m, n and R¹ are as defined herein.

The method may further comprise hydrolizying a compound of formula c

to form the compound of formula d

wherein m, n, R and R¹ are as defined herein.

The method may further comprise reacting a compound of formula a

with a compound of formula b

to form the compound of formula c

wherein m, n, X, R and R¹ are as defined herein.

The invention also provides a compound of formula k1 or k2

wherein:

-   -   m is 0 or 1;    -   n is from 0 to 3;    -   Ar is: aryl; or heteroaryl, each of which may be optionally        substituted with: halo;    -   C₁₋₆alkyl; C₁₋₆alkoxy; cyano; hydroxy; C₁₋₆alkylsulfonyl; or        halo-C₁₋₆alkyl;    -   Y is —O—; —S(O)_(p)— or —N—R^(a) wherein p is from 0 to 2 and        R^(a) is hydrogen or C₁₋₆alkyl; and    -   R¹ is: halo; C₁₋₆alkyl; C₁₋₆alkoxy; or halo-C₁₋₆alkyl.

The invention also provides a compound of formula i

wherein:

-   -   m is 0 or 1;    -   n is from 0 to 3;    -   Ar is: aryl; or heteroaryl, each of which may be optionally        substituted with: halo;    -   C₁₋₆alkyl; C₁₋₆alkoxy; cyano; hydroxy; C₁₋₆alkylsulfonyl; or        halo-C₁₋₆alkyl;    -   Y is —O—; —S(O)_(p)— or —N—R^(a) wherein p is from 0 to 2 and        R^(a) is hydrogen or C₁₋₆alkyl; and    -   R¹ is: halo; C₁₋₆alkyl; C₁₋₆alkoxy; or halo-C₁₋₆alkyl.

Scheme B below illustrates a synthetic route to some preferred compoundsof the invention, wherein:

X is a leaving group;

p is from 1 to 3;

R³ is: halo; C₁₋₆alkyl; C₁₋₆alkoxy; cyano; hydroxy; C₁₋₆alkylsulfonyl;or halo-C₁₋₆alkyl;

R^(f) is C₁₋₆alkyl or —NR^(d)R^(e) wherein R^(d) and R^(e) eachindependently is hydrogen or C₁₋₆alkyl; and

D, E, L, Z, n, R and R¹ are as defined herein.

In step 1 of scheme B, bromofluorophenyl compound q is reacted with angamma-bromo butyrate compound r, to afford gamma-phenyl butyratecompound s. This alkylation reaction may be carried out, for example,under polar aprotic solvent conditions, such as in solution with NMP(N-methylpyrrolidinone). The reaction is carried out in the presence ofzinc and iodine such that an intermediate zincate (not shown) compoundis formed. The reaction is further carried out in the presence of aphosphinylNi(II) catalyst such as bis(triphenylphosphine)Ni(II)chloride.

In step 2 butyrate compound s is hydrolyzed to afford phenyl-butylcarboxylic acid compound t. The hydrolysis may be carried out underaqueous conditions in the presence of NaOH to form the correspondingcarboxylate (not shown), which is then be treated with acid to give thecorresponding carboxylic acid t.

In step 3 a cyclization reaction is carried out in which carboxylic acidcompound t undergoes interal ring closure under anhydrous or dehydratingconditions to form cyclic ketone compound u. The reaction of step 3 mayin many embodiments be carried out in concentrated H₂SO₄.

In step 4, tetralone compound u is reacted with thiophenol compound v toyield phenyl sulfanyl cyclic ketone w. The reaction of step 4 may becarried out in the presence of an amine such as triethylamine, and underpolar aprotic solvent conditions using NMP or a like solvent.

In step 5 cyclic ketone compound w is treated with trimethylsilylcyanate to give dihydronaphthalene carbonitrile compound x. The reactionof step 5 may be carried out in a non-polar solvent such as toluene, andis preferably carried out in the presence of AlCl₃. Carbonitrilecompound x need not be isolated in certain embodiments, and thuscompound x is shown in brackets.

In step 6, dihydronaphthalene carbonitrile compound x is hydrolyzed toafford dihydronaphthalene amide compound y. Hydrolysis in this step maybe achieved using sulfuric acid under aqueous conditions. As notedabove, in certain embodiments nitrile compound x need not be isolated,and the events of steps 5 and 6 may occur in the same reaction vessel.

In step 7, dihydronaphthalene amide compound y is reduced, using chiralruthenium catalyst j1 or j2 in the presence of hydrogen gas, to affordtetralin amide compound z. As noted above, several chiral rutheniumcatalysts j1, j2 may be used for the asymetric reduction of step 7. Useof (S) enantiomer catalyst j1 or j2 in the reduction of step 7 resultsprimarily in (R) product z as shown. Use of (R) enantiomer catalyst j1or j2 results primarily in the corresponding (R) isomer (not shown). Apreferred catalyst j1 for preparing compound z is[Ru(OAc)₂((S)-6,6′-Dimethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine)],also known as [Ru(OAc)₂((S)-MeOBIPHEP)]. The reduction of step 7 may becarried out using a polar aprotic solvent such as tetrahydrofuran (THF).

In step 8, a further reduction is carried out to convert chiral tetralinamide compound z to the corresponding chiral methylamino tetralincompound aa. This reduction may be achieved using borane in a polaraprotic solvent such as THF. The configuration of compound z ispreserved in the reduced product aa. The chiral amide compound z of step7 need not be isolated in certain embodiments and may be reduced in situin step 8.

In step 9, methylamino tetralin compound aa is treated with reagent bbto afford tetralin compound cc. Reagent bb may comprise, for example, anacyl halide such as acetyl chloride or other C₁₋₆carboxylic acidchloride, a urea, or an acyl anhydride such as acetic anhydride or otherC₁₋₆carboxylic acid anhydride. The reaction of step 9 may be carried outin a polar aprotic solvent such as NMP. The configuration of compound aais preserved in the product compound cc.

In step 10 compound cc is treated with peracid, hydrogen peroxide, orlike oxidizing agent to afford sulfonyl compound dd. The configurationof compound cc is preserved in product compound dd.

Accordingly, the invention provides a method of producing a compound offormula z

wherein:

-   -   n is from 0 to 3;    -   p is from 1 to 3;    -   R¹ is: halo; C₁₋₆alkyl; C₁₋₆alkoxy; or halo-C₁₋₆alkyl; and    -   R³ is: halo; C₁₋₆alkyl; C₁₋₆alkoxy; cyano; hydroxy;        C₁₋₆alkylsulfonyl; or halo-C₁₋₆alkyl; the method comprising:

reducing a compound of formula y

with hydrogen gas in the presence of a catalyst of formula j1 or j2

Ru(Z)₂(L)  j1;

Ru(E)(E′)(L)(D)  j2;

wherein:

D is an optionally chiral diamine;

E and E′ are both halo, or E is hydrogen and E′ is BH₄;

L is a chiral diphosphine ligand; and

Z is: halo or R^(b)—CO₂ ⁻ (carboxylate) wherein R^(b) is: C₁₋₆alkyl;halo-C₁₋₆alkyl; C₁₋₆alkoxy; aryl optionally substituted with halo; orheteroaryl optionally substituted with halo.

In certain embodiments, n is 0 or 1.

In certain embodiments, n is 0.

In certain embodiments, n is 1.

In certain embodiments, p is 0 or 1.

In certain embodiments, p is 0.

In certain embodiments, p is 1.

In certain embodiments, R¹ is: fluoro; methyl; methoxy; cyano; hydroxy;methanesulfonyl; or trifluoromethyl.

In certain embodiments, R¹ is fluoro.

In certain embodiments, R³ is: fluoro; methyl; methoxy; cyano; hydroxy;methanesulfonyl; or trifluoromethyl.

In certain embodiments, R³ is fluoro.

In certain embodiments, catalyst j1 is used.

In certain embodiments, catalyst j2 is used.

In certain embodiments, Z is acetate (CH₃COO⁻).

In certain embodiments, the chiral diphosphine L is selected from thegroup consisting of (S)-enantiomers of:

MeOBIPHEP;

(2-Furyl)-MeOBIPHEP);

pTol-MeOBIPHEP;

3,5-Me,4-MeO-MeOBIPHEP;

3,5-iPr,4-MeO-MeOBIPHEP;

3,5-tBu-MeOBIPHEP;

3,5-tBu,4-MeO-MeOBIPHEP;

3,5-TMS-MeOBIPHEP;

TriMeOBIPHEP;

iPr-MeOBIPHEP;

Cy-MeOBIPHEP;

BenzoylOBIPHEP;

BITIANP;

BIPHEMP;

(2-Furyl)-BIPHEMP;

Et-Duphos;

BICP; and

PPF-P(tBu)₂.

In certain embodiments, the chiral diphosphine ligand L is an (R) or(S)-enantiomer of:

MeOBIPHEP;

BIPHEMP;

TMBTP;

2-Naphthyl)-MeOBIPHEP;

(6-MeO-2-Naphthyl)-MeOBIPHEP;

2-(Thienyl)-MeOBIPHEP;

3,5-tBu-MeOBIPHEP;

PHANEPHOS;

BICP;

TriMeOBIPHEP;

(R,R,S,S)-Mandyphos;

BnOBIPHEP;

BenzoylBIPHEP;

pTol-BIPHEMP;

tButylCOOBIPHEP;

iPrOBIPHEP;

p-Phenyl-MeOBIPHEP;

pAn-MeOBIPHEP;

pTol-MeOBIPHEP;

3,5-Xyl-MeOBIPHEP;

3,5-Xyl-BIPHEMP;

BINAP;

2-Furyl-MeOBIPHEP;

3,5-Xyl-4-MeO-MeOBIPHEP;

2-Furyl-MeOBIPHEP; and

BITIANP.

In certain embodiments, the chiral diphosphine ligand L is an (R) or(S)-enantiomer of MeOBIPHEP.

In certain embodiments, the chiral diphosphine L is (S)-MeOBIPHEP.\ Incertain embodiments, the chiral diphosphine L is (R)-MeOBIPHEP.

In certain embodiments, L is(S)-(6,6′-Dimethoxybiphenyl-2,2′-diyl)bisdiphenylphosphine.

In certain embodiments, L is (S)-3,5-Xyl-MeOBIPHEP.

In certain embodiments, the catalyst is [Ru(OAc)₂((S)-MeOBIPHEP)] or[Ru(OAc)₂((R)-MeOBIPHEP)].

In certain embodiments, the catalyst is [Ru(OAc)₂((S)-MeOBIPHEP)].

In certain embodiments, the catalyst is [Ru(OAc)₂((R)-MeOBIPHEP)].

In certain embodiments, catalyst j1 is[Ru(OAc)₂((S)-(6,6′-Dimethoxy-biphenyl-2,2′-diyl)bis(diphenylphosphine))].

In certain embodiments, catalyst j2 is[Ru(OAc)₂((S)-3,5-Xyl-MeOBIPHEP)((R,R)-DPEN)] and the tetralin amidecompound of formula z is produced.

The method of the invention further comprises:

reducing a compound of formula z

to provide a compound of formula aa

wherein n, p, R¹ and R³ are as defined herein.

In certain embodiments the reducing of the compound of formula z iscarried out using borane.

The method of the invention may further comprise:

reacting a compound of formula aa

with a reagent of formula bb

wherein:

-   -   X is a leaving group; and    -   R^(f) is C₁₋₆alkyl or —NR^(d)R^(e) wherein R^(d) and R^(e) each        independently is hydrogen or C₁₋₆alkyl; and    -   to form a compound of formula cc

wherein n, p, R′, R³ and R^(f) are as defined herein.

In certain embodiments the leaving group X is halo.

In certain embodiments the compound of formula bb is acetyl chloride.

In certain embodiments the compound of formula bb is urea.

In certain embodiments the compound of formula bb is acetic anhydride.

In certain embodiments R^(f) is C₁₋₆alkyl.

In certain embodiments R^(f) is NR^(d)R^(e) wherein R^(d) and R^(e) eachindependently is hydrogen or C₁₋₆alkyl.

In certain embodiments R^(f) is —NH₂.

In certain embodiments R^(f) is methyl.

The method may further comprise:

oxidizing a compound of formula cc

to form a compound of formula dd

wherein n, p, R¹, R³ and R^(f) are as defined herein.

The method may further comprise oxidizing/hydrolyzing adihydronaphthalene carbonitrile compound x

to form the compound of formula y

wherein n, p, R¹, and R³ are as defined herein.

The method may further comprise reacting a compound of formula w

with trimethylsilyl cyanide, to afford the compound of formula x

wherein n, p, R¹ and R² are as defined herein.

The method may further comprise reacting a compound of formula e

with a compound of formula v

to form the compound of formula w

wherein n, p, R¹ and R² are as defined herein.

The method may further comprise cyclizing a compound of formula t

to form the compound of formula u.

wherein n and R¹ are as defined herein.

The method may further comprise hydrolyzing a compound of formula c

to form the compound of formula t

wherein n, R and R¹ are as defined herein.

The method may further comprise reacting a compound of formula q

with a compound of formula r

to form the compound of formula s

wherein n, R and R¹ are as defined herein.

The invention also provides a compound of formula z

wherein:

-   -   n is from 0 to 3;    -   p is from 1 to 3;    -   R¹ is: halo; C₁₋₆alkyl; C₁₋₆alkoxy; or halo-C₁₋₆alkyl; and    -   R³ is: halo; C₁₋₆alkyl; C₁₋₆alkoxy; cyano; hydroxy;        C₁₋₆alkylsulfonyl; or halo-C₁₋₆alkyl.

The invention also provides a compound of formula y

wherein:

-   -   n is from 0 to 3;    -   p is from 1 to 3;    -   R¹ is: halo; C₁₋₆alkyl; C₁₋₆alkoxy; or halo-C₁₋₆alkyl; and    -   R³ is: halo; C₁₋₆alkyl; C₁₋₆alkoxy; cyano; hydroxy;        C₁₋₆alkylsulfonyl; or halo-C₁₋₆alkyl.

Specific details for the methods of the invention are described in theExamples section below.

Catalysts:

Ruthenium catalysts suitable for use with the methods of the inventionmay be represented by formula j

Ru(Z)₂L  j1;

wherein:

-   -   Z is: halo; or R^(b)—CO₂ ⁻ where R^(b) is: C₁₋₆alkyl;        halo-C₁₋₆alkyl; C₁₋₆alkoxy; aryl optionally substituted with        halo; or heteroaryl optionally substituted with halo; and    -   L is a chiral diphosphine ligand.

The ruthenium complex catalysts are characterized by the oxidationnumber II. Such ruthenium complexes can optionally comprise furtherligands, either neutral or anionic. Examples of such neutral ligands aree.g. olefins, e.g. ethylene, propylene, cyclooctene, 1,3-hexadiene,norbornadiene, 1,5-cyclooctadiene, benzene, hexamethylbenzene,1,3,5-trimethylbenzene, p-cymene, or also solvents such as e.g.tetrahydrofuran, dimethylformamide, acetonitrile, benzonitrile, acetoneand methanol. Examples of such anionic ligands are CH₃COO⁻, CF₃COO⁻ orhalides. If the ruthenium complex is charged, non coordinating anionssuch as halides, BF₄ ⁻, ClO₄ ⁻, SbF₆ ⁻, PF₆ ⁻, B(phenyl)₄ ⁻,B(3,5-di-trifluoromethyl-phenyl)₄ ⁻, CF₃SO₃ ⁻, C₆H₅SO₃ ⁻ are present.

The ruthenium complex catalysts can be prepared, for example in themanner described by: N. Feiken et al., Organometallics 1997, 16, 537; M.P. Fleming et al., U.S. Pat. No. 6,545,165 (preparation and isolation ofchiral ruthenium dicarboxylate diphosphine complexes); B. Heiser et al.,Tetrahedron: Asymmetry 1991, 2, 51 (in-situ preparation of the samecarboxylato complexes); or J.-P. Genet, Acc. Chem. Res. 2003, 36, 908,the disclosures of which are incorporated herein by reference. U.S. Pat.No. 6,545,165 in particular illustrates preparation of chiral rutheniumdicarboxylate diphosphines.

The ruthenium complex catalysts can be prepared in situ, i.e. justbefore use and without isolation. The solution in which such a catalystis prepared can already contain the substrate for the enantioselectivehydrogenation or the solution can be mixed with the substrate justbefore the hydrogenation reaction is initiated.

Surprisingly, it has been found that also ruthenium phosphine complexesof formula j2 may be used with the invention;

Ru(E)(E′)(L)(D)  j2

wherein E and E′ are both halo or E is hydrogen and E′ is BH₄; L is achiral diphosphine ligand; and D is an optionally chiral diamine.

Complexes of type j2 can be specifically prepared, isolated andcharacterized in analogy to the methods described in Angew. Chem. Int.Ed. 1998, 37, 1703-1707 and in the references cited therein, or can beprepared “in situ” from components as described in above mentionedreference, and be employed without intermediate isolation in thecatalytic asymmetric hydrogenation. When the complexes of type j2 areprepared “in situ”, the amount of chiral diphosphine ligand (L) used inthe reaction can vary from 0.5 to 2.5 equivalents relative to ruthenium,preferably from 0.8 to 1.2 equivalents. Analogously the amount of chiraldiamine can vary from 0.5 to 2.5 equivalents based on the amount of theruthenium-complex, preferably 1 to 2 equivalents.

The reaction may be carried out in presence of chiral diamines asdepicted below;

Further suitable chiral diamines are propane- and butanediamines. Anespecially preferred chiral diamine is DPEN (V), (R,R) or(S,S)-1,2-diphenyl-ethylenediamine. The chiral diamines are commerciallyavailable or can be prepared according to known methods.

In certain embodiments the chiral diphosphine ligand L of catalyst j1,j2 may be characterized by one of formulas (3), (4), (5), (6), (7), (8),(9), (10), (11), (12) or (13):

wherein

-   R⁴ is C₁₋₆alkyl;-   R⁵ is C₁₋₆alkyl;-   R⁶ is independently in each occurrence aryl, heteroaryl,    C₃₋₆cycloalkyl or C₁₋₆alkyl;-   R⁷ is —N(C₁₋₆alkyl)₂ or piperidinyl;-   R⁸ is C₁₋₆alkyl, C₁₋₆alkoxy, hydroxy or C₁₋₆alkyl-C(O)O—; or the two    R⁸ substituents can be joined by a —O(CH₂)_(n)—O— bridge wherein n=2    to 5;-   R⁹ and R¹⁰ independently are hydrogen, C₁₋₆alkyl, C₁₋₆alkoxy or    di(C₁₋₆alkyl)amino; or-   R⁸ and R⁹ which are attached to the same phenyl group, or R⁹ and R¹⁰    which are attached to the same phenyl group, or both R⁸, taken    together, are -A-(CH₂)_(n)-E-, wherein A is —O— or —C(O)O—, E is —O—    or —N(C₁₋₆alkyl)- and n is an integer from 1 to 6, or a CF₂ group;    or-   R⁸ and R⁹, or R⁹ and R¹⁰, together with the carbon atoms to which    they are attached, may form a naphthyl, tetrahydronaphthyl or    dibenzofuran ring;-   R¹¹ and R¹² each independently is C₁₋₆alkyl, C₃₋₆cycloalkyl, phenyl,    napthyl or heteroaryl, substituted with 0 to 3 substituents    independently selected from the group consisting of C₁₋₆alkyl,    C₁₋₆alkoxy, di(C₁₋₆alkyl)amino, morpholino, phenyl and    tri(C₁₋₆alkyl)silyl;

If R¹¹ is phenyl, it is substituted with 0 to 3 substituents asdescribed above.

In certain embodiments, the chiral diphosphine ligand L is characterizedby formula (7), (9), (10) or (12), and wherein Z is CH₃COO, CF₃COO or ahalogenide.

In certain embodiments, the chiral diphosphine L is selected from thegroup consisting of (R) or (S)-enantiomers of:

MeOBIPHEP;

(2-Furyl)-MeOBIPHEP);

pTol-MeOBIPHEP;

3,5-Me,4-MeO-MeOBIPHEP;

3,5-iPr,4-MeO-MeOBIPHEP;

3,5-tBu-MeOBIPHEP;

3,5-tBu,4-MeO-MeOBIPHEP;

3,5-TMS-MeOBIPHEP;

TriMeOBIPHEP;

iPr-MeOBIPHEP;

Cy-MeOBIPHEP;

BenzoylOBIPHEP;

BITIANP;

BIPHEMP;

(2-Furyl)-BIPHEMP;

(R,R)-Et-Duphos;

(all-S)-BICP; and

((S,R)-PPF-P(tBu)₂.

More preferably, the chiral diphosphine is selected from:

MeOBIPHEP;

pTol-MeOBIPHEP;

3,5-iPr,4-MeO-MeOBIPHEP; and

3,5-tBu,4-MeO-MeOBIPHEP

In certain embodiments, the chiral diphosphine ligand L is an (R) or(S)-enantiomer of:

MeOBIPHEP;

BIPHEMP;

TMBTP;

2-Naphthyl)-MeOBIPHEP;

(6-MeO-2-Naphthyl)-MeOBIPHEP;

2-(Thienyl)-MeOBIPHEP;

3,5-tBu-MeOBIPHEP;

PHANEPHOS;

BICP;

TriMeOBIPHEP;

(R,R,S,S)-Mandyphos;

BnOBIPHEP;

BenzoylBIPHEP;

pTol-BIPHEMP;

tButylCOOBIPHEP;

iPrOBIPHEP;

p-Phenyl-MeOBIPHEP;

pAn-MeOBIPHEP;

pTol-MeOBIPHEP;

3,5-Xyl-MeOBIPHEP;

3,5-Xyl-BIPHEMP;

BINAP;

2-Furyl-MeOBIPHEP;

3,5-Xyl-4-MeO-MeOBIPHEP;

2-Furyl-MeOBIPHEP; and

BITIANP.

In certain embodiments, the chiral diphosphine ligand L is an (R) or(S)-enantiomer of MeOBIPHEP.

In certain embodiments, the chiral diphosphine L is (S)-MeOBIPHEP.\

In certain embodiments, the chiral diphosphine L is (R)-MeOBIPHEP.

In certain embodiments, L is (S)-3,5-Xyl-MeOBIPHEP.

In certain embodiments, the catalyst is [Ru(OAc)₂((S)-MeOBIPHEP)] or[Ru(OAc)₂((R)-MeOBIPHEP)].

In certain embodiments, the catalyst is [Ru(OAc)₂((S)-MeOBIPHEP)].

In certain embodiments, the catalyst is [Ru(OAc)₂((R)-MeOBIPHEP)].

Definitions for the above abbreviations used for ligands, as well asliterature and commercial sources, are provided in Table 1 below.

TABLE 1 TABLE 1 LIGANDS IN THE EXAMPLES 1) MeOBIPHEP(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine) (prepared asdescribed in EP 0 398 132, WO 92/16535, EP 0 104 375 or EP 0 580 331) 2)2-Furyl-MeOBIPHEP(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis(di-2-furylphosphine) (prepared asdescribed in EP 0 398 132, WO 92/16535, EP 0 104 375 or EP 0 580 331) 3)pTol-MeOBIPHEP(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis[di(p-tolyl)phosphine] (prepared asdescribed in EP 0 398 132, WO 92/16535, EP 0 104 375 or EP 0 580 331) 4)3,5-Me,4-MeO-(6,6′-Dimethoxy[1,1′-biphenyl]-2,2′-diyl)bis[bis(3,5-di-tert- MeOBIPHEPbutyl-4-methoxyphenyl)phosphine) (prepared as described in EP 0 398 132,WO 92/16535, EP 0 104 375 or EP 0 580 331) 5) 3,5-ipr,4-MeO-(6,6′-Dimethoxy[1,1′-biphenyl]-2,2′-diyl)bis[bis(3,5-di-iso- MeOBIPHEPpropyl-4-methoxyphenyl)phosphine) 6) 3,5-tBu-MeOBIPHEP(6,6′-Dimethoxy[1,1′-biphenyl]-2,2′-diyl)bis[bis(3,5-di-tert-butyl-phenyl)phosphine) (prepared as described in EP 0 398 132, WO92/16535, EP 0 104 375 or EP 0 580 331) 7) 3,5-tBu,4-MeO-(6,6′-Dimethoxy[1,1′-biphenyl]-2,2′-diyl)bis[bis(3,5-di-tert- MeOBIPHEPbutyl-4-methoxyphenyl)phosphine) 8) 3,5-TMS-(6,6′-Dimethoxy[1,1′-biphenyl]-2,2′-diyl)bis[bis(3,5-bis- MeOBIPHEPtrimethylsilyl-phenyl)phosphine) 9) TriMeOBIPHEP Phosphine,(4,4′,5,5′,6,6′-hexamethoxy[1,1′-biphenyl]-2,2′- diyl)bis[diphenyl](prepared as described in EP 0 398 132, WO 92/16535, EP 0 104 375 or EP0 580 331) 10) iPr-MeOBIPHEP2,2-Bis-(diisopropylphosphino)-6,6-dimethoxy-1,1′-biphenyl (preparationdescribed in Schmid et al., Pure and Applied Chemistry 1996, 68(1),131-8) and in Foricher et al. PCT Int. Appl. (1993), WO 9315091 A1) 11)Cy-MeOBIPHEP(2,2-Bis-(dicyclohexylphosphino)-6,6-dimethoxy-1,1′-biphenyl(preparation described in Schmid et al., Pure and Applied Chemistry1996, 68(1), 131-8) and in Foricher et al. PCT Int. Appl. (1993), WO9315091 A1) 12) BenzoylBIPHEP(6,6′-Dibenzoyloxybiphenyl-2,2′-diyl)bis(diphenylphosphine) (Prepared asdescribed in WO 2002012253) 13) BITIANP3,3′-bis-diphenylphosphanyl-1H,1′H-[4,4′]-biisothiochromenyl (preparedas described by Benincori, T.; Brenna, E.; Sannicolo, F.; Trimarco, L.;Antognazza, P.; Cesarotti, E.; Demartin, F.; Pilati, T. J. Org. Chem.1996, 61, 6244) 14) BIPHEMP(6,6′-Dimethylbiphenyl-2,2′-diyl)bis(diphenylphosphine) (prepared asdescribed in EP 0 398 132, WO 92/16535, EP 0 104 375 or EP 0 580 331)15) (2-Furyl)- (6,6′-Dimethylbiphenyl-2,2′-diyl)bis(di-2-furylphosphine)BIPHEMP) (prepared as described in EP 0 398 132, WO 92/16535, EP 0 104375 or EP 0 580 331) 16) Et-Duphos1,2-Bis((2,5-diethylphospholano)benzene Commercially available fromSigma-Aldrich, P O Box 14508, St. Louis, MO, 63178, USA 17) BICP2,2′-bis(diphenylphosphino)-(1S,1′S,2S,2′S)-1,1′-bicyclopentyl(Commercially available from Chiral Quest Inc., Princeton CorporatePlaza, Monmouth Jct., NJ08852, USA) 18) PPF-P(tBu)₂1-[(2-Diphenylphosphino)ferrocenyl]ethyldi-tert.-butyl- phosphine(Commercially available from Solvias AG Basel Switzerland)

The hydrogenation is preferably carried out in an organic solvent whichis inert under the reaction conditions. As such solvents there can bementioned, in particular, lower alcohols such as e.g. methanol, ethanolor isopropanol, trifluoroethanol, ethers such as e.g. diethyl ether,tetrahydrofuran or dioxane, or mixtures of such alcohols withhalogenated hydrocarbons such as methylene chloride, chloroform,hexafluorobenzene and the like or with ethers such as diethyl ether,tetrahydrofuran or dioxane. Preferred solvents for the reaction arelower alcohols, especially preferred is methanol, or ethers, especiallypreferred is tetrahydrofuran. The reaction is carried out at aconcentration of about 1 to 50%, ideally about 5 to 30%

The substrate/catalyst ratio (S/C ratio) is 100-100,000, preferably500-30,000. The hydrogenation is carried out at a pressure of 1 to 300bar, ideally at a pressure of about 1 to 50 bar and at a temperature ofabout 0° C. to about 150° C., ideally at 20° C. to 100° C.

The asymmetric hydrogenations can be carried out either batchwise or ina continuous manner.

Utility

The methods and compounds of the invention are useful for preparation ofcompounds that in turn are usable for the treatment of central nervoussystem diseases, conditions and disorders, including Parkinson'sdisease, Huntington's disease, anxiety, depression, manic depression,psychosis, epilepsy, obsessive compulsive disorders, mood disorders,migraine, Alzheimer's disease (enhancement of cognitive memory), sleepdisorders, feeding disorders such as anorexia, bulimia, and obesity,panic attacks, akathisia, attention deficit hyperactivity disorder(ADHD), attention deficit disorder (ADD), withdrawal from drug abusesuch as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia,and also disorders associated with spinal trauma and/or head injury suchas hydrocephalus. The methods are particularly useful for preparation ofcompounds for treatment of memory disorders, for enhancing cognition,and for enhancing cognition in Alzheimer's patients.

EXAMPLES

The following examples are given to enable those skilled in the art tomore clearly understand and to practice the present invention. Theyshould not be considered as limiting the scope of the invention, butmerely as being illustrative and representative thereof. The followingabbreviations may be used in the Examples.

Abbreviations

HPLC high pressure liquid chromatography

DABN 2,2′-Diamino-1,1′-binaphthalene

DACH trans-1,2-Diaminocyclohexan

DAIPEN 1,1-Di(p-methoxyphenyl)-2-isopropylethylenediamine

DCEN 1,2-Dicyclohexane-ethylendiamine

DCM dichloromethane/methylene chloride

DMF N,N-dimethylformamide

DMAP 4-dimethylaminopyridine

DTBEN 1,2-Di-tert.-butylethylenediamine

EtOAc ethyl acetate

EtOH ethanol

Et₂O diethyl ether

GC gas chromatography

HMPA hexamethylphosphoramide

hplc high performance liquid chromatography

IPA isopropanol

mCPBA m-chloroperbenzoic acid

MeCN acetonitrile

MeOH methanol

MTBE methyl tert-butyl ether

NMP N-methylpyrrolidinone

TEA triethylamine

THF tetrahydrofuran

LDA lithium diisopropylamine

TLC thin layer chromatography

TMSCN trimethylsilyl cyanate

S/C Substrate-to-catalyst molar ratio

DPEN 1,2-Diphenyl-ethylenediamine

Example 1[(R)-6-(3-Fluoro-phenylsulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-urea

The synthetic procedure used in this Example is outlined in Scheme C.

Step 1 4-(3-Fluoro-phenyl)-butyric acid ethyl ester

A slurry of zinc powder (1.44 kg, 1.2 eq, 100 mesh) in anhydrous1-methyl-2 pyrrolidinone (7.3 kg) was treated with iodine (226 g) in achemical reactor. An exotherm to about 40° C. occurred and the iodinecolor disappeared. With good agitation the temperature was raised toabout 60° C. and ethyl 4-bromobutyrate (4.2 kg) was charged whilemonitoring for an exotherm above the reactor jacket temperature. Thereaction was initiated by adding one kg of ethyl 4-bromobutyrate andheating the jacket to about 55° C. Reaction onset was detected at about55° C. The reaction temperature was controlled incrementally from 60 toabout 95° C. by slow addition of the remaining 3.2 kg of ethyl4-bromobutyrate. At the end of the addition the reaction mixture washeated to about 95° C. until the reaction was complete (approximately 2%starting material by GC). Formation of the intermediate zincate (notshown in Scheme C) was confirmed by GC analysis, (a sample aliquot wasquenched into 4N hydrochloric acid and extracted with MTBE). Thereaction mixture was cooled to about 25° C. andbis(triphenylphosphine)nickel(II) chloride 45.8 g added. The reactionmixture was then heated to about 40° C. and 1-bromo-3-fluorobenzene(3.23 kg) was added over a period of about 6 hours. The reactiontemperature was maintained between 35 and 45° C. by controlling theaddition rate of 1-bromo-3-fluorobenzene. The exotherm was monitored bythe temperature differential between the jacket and the reactor internalprobe. Once the addition was complete the reaction mixture was heatedfor 24 hours at 40° C. The reaction was cooled to 15° C. and quenchedwith water (4.5 liters), acidified with 6N aqueous hydrochloric acid (14liters) and stirred until all gas evolution had ceased and all salts haddissolved. The crude reaction mixture was filtered through a bed ofcelite. The celite bed was washed through with MTBE (10 liters) andcharged to an extractor ball. The extractor ball was charged withadditional fresh MTBE (5 liters) and the filtered aqueous reactionmixture was extracted in portions and split off. The organic layer inthe extractor ball was washed with three times with water (5 liters eachtime). The organic layer was separated and concentrated in vacuo and theresulting crude 4-(3-fluoro-phenyl)-butyric acid ethyl ester (10.5-kg),isolated as an oil, was used without further purification in the nextstep: MS (M+1)=210; H¹ NMR (300 MHz): δ ppm (CDCl₃): 1.25(3H, t, J=7.16Hz), 1.94 (2H, dp), 2.31 (2H, t, J=7.54 Hz), 2.65 (2H, t, J=7.54 Hz),4.12 (2H, q, J=7.16), 6.84-6.96 (2H, m), 7.19-7.26 (2H, m).

Step 2 4-(3-Fluoro-phenyl)-butyric acid

Crude 4-(3-fluorophenyl)butyric acid ethyl ester (10.5-kg), water (15.8L) and 50% NaOH (12.0 kg) were charged to a reactor and stirred at 50°C. for 2 hours. The hydrolysis generated a mild exotherm to 55° C. Thebiphasic mixture became monophasic. Completion of the hydrolysis wasconfirmed by LC. The reaction mixture was cooled to 20° C. and washedwith hexanes 15 kg (containing antistatic agent “ASA 3”) to remove3′3-difluorobiphenyl impurity generated in the previous step. Afterphase separation the aqueous layer was acidified with 37% concentratedHCl (16.7 kg), keeping the exotherm below 40° C. Upon cooling theaqueous layer was extracted with MTBE (15 kg in three 5 kg extractions).The solvent was removed by vacuum distillation and excess MTBE removedwith a hexane strip. The resulting 4-(3-fluoro-phenyl)-butyric acid(8.83 kg) was removed from the reactor as an oil and used withoutfurther purification: MS (M+1)=182; H¹ NMR (300 MHz): δ ppm (CDCl₃):1.965 (2H, p, J=4.9, 2.47 hz), 2.37 (2H, t, J=2.47 Hz), 2.66 (2H, t,J=2.45), 6.87 (2H, m), 6.95 (1H, d, J=2.63), 7.22 (1H, m) 11.2(0.2H,bs).

Step 3 6-Fluoro-3,4-dihydro-2H-naphthalen-1-one

Crude 4-(3-fluorophenyl)butyric acid (8.83 kg) was added to concentratedsulfuric acid (30 kg) in a chemical reactor at a rate such that the pottemperature stayed between 40° C. and 60° C. (jacket heating was notnecessary). The reaction was stirred at 45° C. for 3 hours and reactioncompletion was confirmed by LC. The reaction mixture was cooled andquenched with water (16 L), and then extracted with 35% THF in methylenechloride (25.8 kg). The organic layer was separated and washed withwater (16 L), saturated aqueous NaHCO₃ (16.9 kg) and then a mixture ofwater (16.1-kg)/brine (4.7-kg). The organic later was concentrated undervacuum and re-stripped with the aid of hexane to remove water and afford6-fluoro-3,4-dihydro-2H-naphthalen-1-one as an oil (5.88 kg): MS(M+1)=165; H¹ NMR (300 MHz): δ ppm (CDCl₃): 2.14 (2H, m, J=6.03, 5.75Hz), 2.64 (2H, dd, J=6.03, 5.75 Hz); 2.94 (2H, t, J=6.03), 6.9-7.0(2H,m, J=2.26,2.64, 6.03 Hz), 8.02-8.07 (1H, dd, J=6.03).

Step 4 6-(3-Fluoro-phenylsulfanyl)-3,4-dihydro-2H-naphthalen-1-one

A solution of 6-fluoro-3,4-dihydro-2H-naphthalen-1-one (3.64 kg) and3-fluorothiophenol (2.80 kg), in anhydrous NMP (7.7 kg) was treated withtriethylamine (2.26 kg). After a mild exotherm had subsided, the mixturewas heated for 20 hours at 90° C. The mixture was cooled to about 25° C.and diluted with water (30 L) and heptane (10 kg). The mixture wasagitated for 12 hours and then filtered. The filter cake was washed withwater and dried at 60° C. under vacuum to afford6-(3-fluorophenylsulfanyl)-3,4-dihydro-2H-naphthalen-1-one (5.52 kg):MP=66.2-66.7° C.; MS (M+1)=273; H¹ NMR (300 MHz): δ ppm (CDCl₃): 2.10(2H, m, J=6.03, 6.40 Hz), 2.62 (2H, dd, J=6.03, 5.75 Hz) 2.87 (2H, t,J=6.03), 7.03 (1H,tdd, J=1.13, 2.64, 8.29 Hz), 7.08-7.16 (2H, m), 7.22(1H, dt, J=1.13, 8.29 Hz), 7.31 (1H, q, 8.29 Hz), 7.35 (1H, dd, J=5.65,7.91 Hz) 7.92(1H, d, J=7.91 Hz).

Step 5 6-(3-Fluoro-phenylsulfanyl)-3,4-dihydro-naphthalene-1-carboxylicacid amide

6-(3-Fluoro-phenylsulfanyl)-3,4-dihydro-2H-naphthalene-1-one (4.78 kg)was dissolved in toluene (50 kg) and the resulting mixture wasazeotropically distilled under vacuum at 50 to 55° C. untilapproximately 10 L of toluene remained. The solution was cooled to 25°C. and AlCl₃ (52 g) was added. TMSCN (1.85 kg) was added at a rate suchthat the reaction temperature was kept between 20 and 50° C. Thereaction was monitored for completion by TLC (Hexanes/EtOAc 4:1). Theresulting6-(3-Fluoro-phenylsulfanyl)-3,4-dihydro-naphthalene-1-carbonitrile wasnot isolated from the reaction mixture. Once complete the reaction wascooled to 5° C. and sulfuric acid (4.06 kg) was added slowly to maintainan internal temperature below 30° C. The reaction was then diluted withacetic acid (24 kg), sulfuric acid (18 kg) and water (2.4 kg). Thereaction mixture was heated to 105° C. for three hours, then cooled to25° C. and quenched with water (48 kg). The product was filtered andwashed thoroughly with water (28 kg), MTBE (10.6 kg), and dried undervacuum with a nitrogen purge to afford6-(3-fluoro-phenylsulfanyl)-3,4-dihydro-naphthalene-1-carboxylic acidamide as a white solid (4.59-kg): MP=167.9-169.7° C.; MS (M+1)=300; H¹NMR (300 MHz): δ ppm (DMSO): 2.31 (2H, m, J=4.29, 8.29 Hz), 2.72 (1H, t,J=7.91), 3.64 (0.5H, s, NH), 6.54 (1H, t, J=4.52 Hz), 7.02-7.12 (3H, m),7.22 (˜0.5H, bs, NH), 7.25-7.30 (2H, m), 7.35-7.42 (2H, m), 7.52 (1H, d,J=8.67), 7.67 (1H, bs, NH).

Step 6(R)-6-(3-Fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalene-1-carboxylicacid amide

A suspension of6-(3-fluorophenylsulfanyl)-3,4-dihydronaphthalene-1-carboxylic acidamide (2.3 kg) and [Ru(OAc)₂((S)-MeOBIPHEP)] (1.36 g) in THF (25 kg) washydrogenated at 40° C. and 160 psi (11 bar) of hydrogen for 36 hours toafford a solution of(R)-6-(3-fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalene-1-carboxylicacid amide in THF that was used directly in the next step. Analysis ofan aliquot of the THF solution provided the following data:

MP=131.9-132.6° C.; MS (M+1)=302H¹ NMR (300 MHz): δ ppm (DMSO): 1.61(1H, m), 1.92 (2H, m), 2.70 (2H, m), 3.63 (1H, t, J=6.78 Hz), 6.97-7.10(4H, m), 7.13-7.22 (3H, m), 7.33-7.40 (1H, m), 7.50 (1H, NH);[α]_(D)=4.0° (MeOH). Chiral Assay (Area Norm): Column: ChiralCel OD-H(250×4.6 mm), mobile phase 90/10 hexane/ethanol(isocratic), flow rate0.7 ml/min, 25° C., uv @230 nm.: (R)-isomer 98.59/(S)-isomer 1.41.

Step 7[(R)-6-(3-Fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylaminehydrochloride

A solution of(R)-6-(3-fluorophenylsulfanyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylicacid amide (approximately 4.63 kg) in THF was concentrated toapproximately 4 volumes via atmospheric distillation. To the resultingsolution at room temperature was added BH₃THF (1.0 M THF solution; 67.5kg) while venting off hydrogen through a flame arrestor. Followingcompletion of the addition, the reaction mixture was heated to 55° C.and stirred for 40 hours. The reaction mixture was quenched by inverseaddition to cooled (5° C.) 10% aqueous H₂SO₄ (13 kg) in a quench vessel,keeping the vessel temperature below 20° C. The contents of the quenchvessel were then warmed to 25° C. and stirred for 12 hours, then cooledto 5° C. and the pH of the reaction mixture was adjusted to 9-10 byaddition of aqueous ammonium hydroxide (23.4 kg). The reaction mixturewas then warmed to 40° C., and the layers are separated. The organicphase was concentrated to about 4 volumes by atmospheric distillationand isopropyl acetate (94.8 kg) was added. The organic phase was washedwith dilute brine (20.9 kg) and acidified by addition of 6N HCl in IPA(5.25 kg). Distillation of the remaining THF and IPA causedprecipitation of the product. After cooling to 0° C., the product wasisolated by filtration, washed with isopropyl acetate and dried undervacuum at 60° C. to affordC—[(R)-6-(3-Fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylaminehydrochloride (4.64-kg): MP=195.7-196.2° C.; H¹ NMR (300 MHz): δ ppm(DMSO): 1.59-1.99 (3H, m), 2.6-2.80 (2H, m), 2.92 (1H, dd,J=12.81,12.43), 3.06 (1H, dd, J=3.77, 12.81 Hz), 3.24 (1H, m), 6.99-7.12(3H, m), 7.19-7.25 (2H, m), 7.33-7.43 (2H, m), 8.45 (2H, bs, NH);[α]_(D)=−0.3° (MeOH). Chiral Assay (Area Norm): Column: Chiralpak IA(150×4.6 mm), mobile phase 80/20 hexane/ethanol(isocratic), flow rate1.0 ml/min, 25° C., uv @230 nm.: (R)-isomer 99.17/(S)-isomer 0.83.

Step 8[(R)-6-(3-Fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-urea

(R)-6-(3-fluorophenylsulfanyl)-1,2,3,4-tetrahydronaphthalen-1-methylaminehydrochloride salt (4.6 kg) and urea (3.4 kg) were suspended in freshNMP (9.5 kg). Concentrated aqueous 37% HCl (0.15 kg) was added and thereaction mixture was heated to 100° C. for three hours. On completion ofreaction (confirmed by HPLC), the reaction mixture was cooled to 60° C.and water (45 kg) was added. The resulting slurry was stirred vigorouslywhile cooling down to 20° C., and the mixture was allowed to sit for 24hours. The resulting solid was filtered and washed with water. The wetfilter cake was taken into toluene (23.6-kg) and heated to 80° C., thenwashed with water (twice with 13.5 L) and the reaction mixture wascooled to 40° C.[(R)-6-(3-Fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-ureacrystallized on addition of n-heptane (7.8 kg). The product was filteredand dried under reduced pressure at 50° C. to afford 3.78-kg of[(R)-6-(3-fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-urea:MP=115.1-116.0° C.; MS (M+1)=288; H¹ NMR (300 MHz): δ ppm (DMSO):1.59-1.84 (3H, m), 2.59-2.78 (2H, m), 2.86 (1H, m), 3.10 (1H, ddd,J=6.03, 9.04 Hz), 3.28 (1H, ddd, J=5.65, 6.03), 3.34 (1H, s), 5.46 (2H,s, NH), 6.11 (1H, t, J=6.03 Hz) 6.96-7.09 (3H, m), 7.17-7.23 (2H, m),7.26-7.31 (1H, m), 7.32-7.41 (1H, m): [α]_(D)=25.5° (MeOH). Chiral Assay(Area Norm): Column: Chiralpak AS-H (150×4.6 mm), mobile phase 80/20hexane/ethanol(isocratic), flow rate 0.7 ml/min, 25° C., uv @230 nm.:(R)-isomer 99.03/(S)-isomer 0.97.

Step 9[(R)-6-(3-Fluoro-phenylsulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-urea

A suspension of[(R)-6-(3-fluorophenylsulfanyl)-1,2,3,4-tetrahydronaphthalen-1-1y-methyl]urea(3.76 kg) in methylene chloride (71 kg) was treated with 98% formic acid(1.31 kg.) and 30% aqueous hydrogen peroxide (6.63 kg). The biphasicreaction mixture was stirred at 35° C. for 48 hours, and then water (12L) was added. The phases were separated, leaving the aqueous peroxidelayer in the original reactor for treatment with sodiumhydroxide-bisulfite. The organic layer was washed with saturated aqueoussodium bicarbonate (30 kg), water (30 L) and saturated aqueous sodiumchloride (38 kg). The organic layer was checked for peroxide content,and then the methylene chloride layer was distilled off and replacedwith methanol. The methanol was reduced to about 9 liters under reducedpressure, and the resulting solution was filtered hot to a clean reactorand cooled to 25° C. Water (4 L) was slowly added to the cloud point andthe mixture was stirred for three hours until crystallization occurred,and then an additional 6 L of water was added. The product was filteredand washed with chilled filtered methanol-sterile water for irrigation(50:50). The damp cake was dried at 40° C. in a vacuum oven with anitrogen purge to constant weight to afford 3.95 kg of[(R)-6-(3-fluoro-phenylsulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-urea:MP=154.9-156.1° C.; MS (M+1)=362; H¹ NMR (300 MHz): δ ppm(DMSO):1.6-1.82 (3H, m), 2.67-2.83 (1H, m), 2.83-2.96 (1H, m), 3.04-3.14(1H, ddd, J=5.65, 6.03, 8.67 Hz), 3.21-3.3 (1H, ddd, J=4.90, 6.03,8.67Hz), 3.34 (1H, s), 5.46 (2H, s, NH), 6.10 (1H, t, J=5.65 Hz), 7.43-7.47(1H, m), 7.52-7.59 (1H, ddt, J=1.13, 2.64, 8.67 Hz), 7.64-7.76 (3H, m),7.79-7.85 (2H, m); [α]_(D)=25.9° (MeOH). Chiral Assay (Area Norm):(Column: Chiralpak IA (150×4.6 mm), mobile phase Ethanol(isocratic),Flow rate 1.0 ml/min, 25° C., uv @230 nm.: (R)-isomer 99.33/(S)-isomer0.67.

Example 2N#R)-6-Benzenesulfonyl-8-fluoro-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-acetamide

The synthetic procedure used in this Example is outlined in Scheme D.

Step 1 4-(3,5-Difluoro-phenyl)-butyric acid propyl ester

A slurry of zinc powder (1.37-kg 1.5 eq) in anhydrous 1-methyl-2pyrrolidinone (7.38 kg) was treated with iodine (210 g). An exotherm to20-27° C. occurred and the iodine color disappeared. With good agitationthe temperature was raised to 60° C. Ethyl 4-bromobutyrate (4.07 kg) wasincrementally charged to bring the reaction temperature to 88° C.(without heating) and maintained at 90° C. by the addition rate of theremaining ethyl 4-bromobutyrate. Once addition was complete the reactionmixture was heated to 90° C. (until zinc insertion was complete).Formation of the intermediate zincate (not shown) was confirmed by GCanalysis, (samples were quenched into 4N hydrochloric acid and extractedwith MTBE). The reaction mixture was cooled to 20° C. andbis(triphenylphosphine)nickel(II) chloride (80.2 g) was added. Thereaction mixture was then heated to 50° C. and1-bromo-3,5-difluorobenzene (2.71 kg) was added over a period of 6hours. The reaction temperature was maintained at 50° C. by the additionrate of 1-bromo-3,5-difluorobenzene. This exotherm was monitored by thetemperature differential between the jacket and the internal probe. Oncethe addition was complete the reaction mixture was heated for 24 hoursat 40° C. The reaction was cooled to 15° C. and quenched with water (4.8liters), acidified with 6N aqueous hydrochloric acid (14.2 kg) andstirred until all gas evolution had ceased and all salts have dissolved.The aqueous layer was washed with MTBE (8.04 kg) and the phases wereseparated. The organic layer was washed with water (9.75 kg). Theorganic layer was separated and concentrated in vacuo to give 3.3 kg of4-(3,5-difluoro-phenyl)-butyric acid propyl ester as an oil with apurity of 76.2% by AN HPLC: MS (M+1)=228; H¹ NMR (300 MHz): δ (CDCl₃):1.26 (3H, t, J=7.16 Hz), 1.94 (2H, p, J=7.54 Hz), 2.32 (2H, t, J=7.54Hz), 2.64 (2H, t, J=7.54 Hz), 4.14 (2H, q, J=7.16 Hz), 6.62 (1H, tt,J=2.26, 9.04 Hz), 6.70 (2H, m, J=1.88, 2.26, 6.4 Hz).

Step 2 4-(3,5-Difluoro-phenyl)-butyric acid

A mixture of crude 4-(3,5-difluoro-phenyl)-butyric acid propyl ester(3.3 kg), water (4.4 kg), and 50% sodium hydroxide (3.35 kg) werestirred at 50° C. for 1 hour. The hydrolysis was monitored by HPLC. Theresulting solution was washed with hexane (4.2 kg) to remove organicimpurities. The aqueous layer was acidified with conc. HCl (4.73 kg),and extracted with MTBE (4.23 kg). The solution was concentrated, andresidual MTBE was removed by solvent exchange with n-heptane (4.0liters) to give crude 4-(3,5-difluoro-phenyl)-butyric acid (2.8 kg) asan oil: H¹ NMR (300 MHz): δ (CDCl₃): 1.94 (2H, p, J=7.54 Hz), 2.38 (2H,t, J=7.54 Hz), 2.65 (2H, t, J=7.54 Hz), 6.63 (1H, tt, J=2.26, 9.04 Hz),6.7 (2H, m, J=2.26, 6.4 Hz), 11.70 (1H, bs, COOH)

Step 3 6,8-Difluoro-3,4-dihydro-2H-naphthalen-1-one

A mixture of concentrate sulfuric acid (10.21 kg) and crude4-(3,5-difluoro-phenyl)-butyric acid (2.8 kg) was stirred at 45° C.until the cyclization reaction was complete by HPLC. The reactionmixture was diluted with water (6.15 kg), and the product was extractedwith THF/methylene chloride (2.71/7.33 kg) mixture. The organic layerwas sequentially washed with water (4 liters), saturated aqueous sodiumbicarbonate (2.64 kg), water (3.0 kg) and 50% diluted brine (8.4 kg).Removal of the solvents provided 1.64 kg (62% yield) of6,8-difluoro-3,4-dihydro-2H-naphthalen-1-one as a light yellow solid(92.75% pure by HPLC): MP=58.1-58.8° C.; MS (M+1)=183; H¹ NMR (300 MHz):δ (DMSO): 2.00 (2H, p, J=6.4 Hz), 2.57 (2H, t, J=6.40 Hz), 2.96 (2H, t,J=6.40 Hz), 7.08-7.20 (2H, m, J=2.26 Hz).

Step 4 8-Fluoro-6-phenylsulfanyl-3,4-dihydro-2H-naphthalen-1-one

A solution of 6,8-difluoro-3,4-dihydro-2H-naphthalen-1-one (1.58 kg) inN,N-dimethylacetamide (4.65 liters) was treated with triethylamine (877g) and thiophenol (954.9 g) at 20° C. and the reaction mixture wasstirred for 19 hours. The reaction mixture was treated with heptane(2.38 liters.), followed by water (9.5 liters) and the precipitate wasisolated by filtration and the resulting slurry washed with twice withheptane (790 ml each time), three times with water (1.0 liters eachtime) and five times with cyclohexane (1.0 liters, each time). Theslurry was dried to give8-fluoro-6-phenylsulfanyl-3,4-dihydro-2H-naphthalen-1-one (1.86 kg, 79%yield) with a purity of 96.2% by HPLC, together with 3.6% yield of theisomer 6-fluoro-8-phenylsulfanyl-3,4-dihydro-2H-naphthalen-1-one:MP=111.7-112.7° C.; MS (M+1)=273; H¹ NMR (300 MHz): δ (DMSO): 1.96 (2H,p, J=6.4 Hz), 2.53 (2H, t, J=6.03 Hz), 2.84 (2H, t, J=6.03 Hz), 6.69(1H, dd, J=1.51, 12.06 Hz), 6.91 (1H, d, J=1.13 Hz), 7.5-7.61 (5H, m,Phenyl).

Step 5 8-Fluoro-6-phenylsulfanyl-3,4-dihydro-naphthalene-1-carboxylicacid amide

8-Fluoro-6-phenylsulfanyl-3,4-dihydro-2H-naphthalen-1-one (1.855 kg,6.793 moles) from step 4 was dissolved in toluene (3.2 kg) and resultingmixture was distilled under vacuum at 50-55° C. until approximately 2 kgof toluene was removed. The remaining solution was cooled to 20° C. andAlCl₃ (37 g) was added. TMSCN (96%, 0.7 kg, 1.0 equiv.) was added overone hour at such a rate that the reaction temperature was kept between20-50° C. The reaction was monitored for completion by TLC(hexanes/EtOAc 4:1) confirming formation of8-fluoro-6-phenylsulfanyl-3,4-dihydro-naphthalene-1-carbonitrile, whichwas not isolated.

The reaction mixture was then cooled to 5° C. and sulfuric acid (1.7 kg)was added slowly, maintaining the internal temperature below 30° C.After 10 minutes the reaction was diluted with acetic acid (9.25 kg, 5.0vol.), sulfuric acid (6.8 kg, 2.0 vol.) and water (0.93 kg, 0.5 vol).The reaction mixture was then heated to 105° C. while monitoring thereaction progression by HPLC. Once complete (2.0 hours) the reaction wascooled and water (10 vol.) was added. The product was filtered andwashed twice with water (5.5 kg each time) and then triturated in areactor with EtOAc (17 kg) under reflux for 1 hour. The resulting slurrywas cooled, filtered and rinsed with twice EtOAc (1.7 kg each time). Theproduct was dried at 35° C. under vacuum to give 1.56 kg of8-fluoro-6-phenylsulfanyl-3,4-dihydro-naphthalene-1-carboxylic acidamide (77%, 98.3% pure by HPLC): MP=223.6-225.9° C.; MS (M+1)=300; H¹NMR (300 MHz): δ (DMSO): 2.22 (2H, dt, J=7.54 Hz), 2.64 (2H, t, J=7.54Hz), 6.47 (1H, t, J=4.90 Hz), 6.83 (1H, dd, J=1.88, 10.93 Hz), 7.0 (1H,m), 7.08 (1H, bs, NH), 7.35-7.45 (5H, m, Phenyl), 7.55 (1H, bs, NH).

Step 6((R)-8-Fluoro-6-phenylsulfanyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methylaminehydrochloride

A suspension of8-fluoro-6-phenylsulfanyl-3,4-dihydro-naphthalene-1-carboxylic acidamide (1.46 kg) in methanol (23.2 kg) and [Ru(OAc)₂((S)-MeOBIPHEP)](1.83 g) in methanol (1.5 liters) were combined and subjected tohydrogenation at 40° C. and 150 psig (10.3 bar). Completion of thereaction to form(R)-8-fluoro-6-phenylsulfanyl-1,2,3,4-tetrahydro-naphthalene-1-carboxylicacid amide (not isolated) was monitored by HPLC. The resulting reactionsolution was distilled and the solvent exchanged from methanol to THF(7.6 kg). Analysis of an aliquot of the THF solution provided thefollowing data: MP=167.4-168.2° C.; MS (M+1)=302; H¹ NMR (300 MHz): δ(DMSO): 1.56-1.84 (2H, m), 1.91 (2H, m), 2.66 (2H, m), 3.67 (1H, t,J=5.65 Hz), 6.80 (1H, dd, J=1.88, 10.17 Hz), 6.88 (1H, bs, NH), 6.92(1H, m), 7.32-7.44 (6H, m, Phenyl, NH): [α]_(D)=30.5° (MeOH). ChiralAssay (Area Norm): Column: ChiralCel OD-H (250×4.6 mm), mobile phase85/15 hexane/ethanol(isocratic) Flow rate 0.7 ml/min, 25° C., uv @230nm.: (R)-isomer 99.32/(S)-isomer 0.68.

The THF solution was treated with Borane THF complex (1.0M THF solution,22.3 kg) and the resulting reaction mixture was heated to 55° C. at 5psig for 20 hours. The reaction mixture was then slowly charged into a10% aqueous sulfuric acid solution (24.3 kg) while keeping thetemperature between 5 and 10° C. The resulting solution was treated with28% aqueous ammonium hydroxide solution (7.05 kg) to adjust the pH toabout 10, and was then heated to 40° C. The biphasic system wasseparated and the organic layer was atmospherically distilled to removeTHF solvent, which was then replaced with isopropyl acetate (12.8 kg).The solution was sequentially washed with water (4.0 kg) and brine (5.1kg). The solution was then cooled to 5° C. and treated with 6N HCl inisopropanol (1.69 kg). The mixture was heated and atmosphericallydistilled and the solvent was distilled to 90° C. and replaced withisopropyl acetate. The resulting solid was isolated by filtration,washed with chilled isopropyl acetate (3.84 kg), and dried under vacuumto affordC—((R)-8-fluoro-6-phenylsulfanyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methylaminehydrochloride (1.38 kg), 87.8% yield, purity 99.5% by HPLC, Chiral HPLC96.88% ee: MP=232.5-233.8° C.; MS (M+1)=288; H¹ NMR (300 MHz): δ (DMSO):1.55-1.78 (3H, m), 2.08 (1H, bd), 2.55-2.80 (2H, m), 2.89 (2H, bs), 3.31(1H, bt), 6.85 (1H, dd J=1.51, 10.55 Hz), 6.91 (1H, s), 7.33-7.46 (5H,m), 8.37 (2H, bs, NH₂); [α]_(D)=31.8° (MeOH). Chiral Assay (Area Norm):Column: Chiralpak AD-H (150×4.6 mm), mobile phase 95/5 hexane/ethanolwith 0.1% isopropylamine(isocratic) Flow rate 0.7 ml/min, 25° C., uv@230 nm.: (R)-isomer 98.44/(S)-isomer 1.56.

Step 7N—((R)-8-Fluoro-6-phenylsulfanyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-acetamide

A mixture ofC—((R)-8-fluoro-6-phenylsulfanyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methylaminehydrochloride (1.36 kg), DMAP (10 g), acetonitrile (8.6 L),triethylamine (1.27 L), and acetic anhydride (0.41 L) was stirred at 25°C. After thirty minutes water (17.5 L) was added. The resulting slurrywas stirred for 30 minutes at 25° C. The product was isolated byfiltration and washed with 7.5 L of water. Drying overnight at 50° C.provided 1.34 kg ofN#R)-8-fluoro-6-phenylsulfanyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-acetamide(97.4% yield, 99.66% pure by HPLC, 98.08% ee): MP=94.6-95.9° C.; MS(M+1)=330; H¹ NMR (300 MHz): δ (DMSO): 1.44-1.91 (4H, m), 1.83 (3H, s),2.54-2.79 (2H, m), 3.06 (1H, m), 3.16 (2H, m), 6.83 (1H, dd, =1.51,10.17 Hz), 6.90 (1H, bs), 7.30-7.45 (5H, m, phenyl), 8.01 (1H, bt,J=5.65 Hz, NH); [α]_(D)=7.4° (MeOH). Chiral Assay (Area Norm): Column:Chiralpak AD-H (150×4.6 mm), mobile phase 88/12hexane/ethanol(isocratic) Flow rate 0.7 ml/min, 25° C., uv @230 nm.:(R)-isomer 99.04/(S)-isomer 0.96

Step 8N—((R)-8-Fluoro-6-phenylsulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-acetamide

N—((R)-8-Fluoro-6-phenylsulfanyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-acetamide(1.32 kg) was suspended in methylene chloride (8 liters) and treatedwith 98% formic acid (455 g). The resulting solution is treated with 30%hydrogen peroxide (2.38 kg) in two portions. The temperature wasmonitored after the addition of the first portion of peroxide and whenthe temperature stabilized the second portion was added. The reactionmixture was stirred for 23 hours. A fresh charge of formic acid (230-g)and hydrogen peroxide (1.32 kg) was added and the reaction mixture wasstirred an additional 12 hours. When the reaction was complete by HPLC,water (1.8 liters) was added and the phases were separated. Themethylene chloride layer was washed with saturated sodium bicarbonatesolution (5 kg), water (three times 5 liters each time) until theaqueous layer tested negative for peroxide content. The methylenechloride layer was washed with brine (6.54 kg) and concentrated underreduced pressure. The solvent was replaced with methanol. The weight ofthe residual methanol was adjusted to match the starting input (1.3-kg).The resulting solution was filtered and the solution was treated tocloud point with sterile water to allow crystallization to occur overfour hours. More sterile water for irrigation was added until 3.38 kgtotal had been added and the mixture was stirred until it returned toroom temperature. The product was filtered and washed withmethanol/sterile water (1:2) and dried under vacuum oven at 50° C. toconstant weight to affordN#R)-8-fluoro-6-phenylsulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-acetamide(1.4 kg), 99.8% pure by HPLC, Chiral Assay: 98.54% ee R-isomer:MP=152.5-153.8° C.; MS (M+1)=362; H¹ NMR (300 MHz): δ (DMSO): 1.45-1.93(4H, m), 1.84 (3H, s), 2.74 (1H, dq, J=6.03, 10.55 Hz), 2.91 (1H, bdt),3.17 (3H, m), 7.54-7.75 (5H, m, phenyl), 8.01 (1H, dd, J=1.88, 7.53 Hz),8.06 (1H, bt, NH); [α]_(D)=39.7° (MeOH). Chiral Assay (Area Norm):Column: Chiralpak IA (150×4.6 mm), mobile phase 20/40/40hexane/ethanol/methanol(isocratic) Flow rate 0.7 ml/min, 25° C., uv @230nm.: (R)-isomer 99.27/(S)-isomer 0.73.

Example 3[(R)-8-Fluoro-6-(3-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-urea

The synthetic procedure used in this Example is outlined in Scheme E.

Step 18-Fluoro-6-(3-fluoro-phenylsulfanyl)-3,4-dihydro-2H-naphthalen-1-one

A solution of 6,8-difluoro-3,4-dihydro-2H-naphthalen-1-one (50 g) in N,N′dimethylacetamide (100 ml) was treated with triethylamine (38.2 ml),followed by 3-fluorothiophenol (28.2 ml), keeping the temperature below20° C. The reaction mixture was allowed to stir at ambient temperaturefor 18 hours. The reaction was diluted with MTBE (70 ml) and cooled onan ice-bath. Water (300 ml) was slowly added (keeping temperature below25° C.) and the mixture aged for 1 hour. The product was collected byfiltration and washed with water and cyclohexane, and dried to afford8-fluoro-6-(3-fluoro-phenylsulfanyl)-3,4-dihydro-2H-naphthalen-1-oneas apale yellow solid yield (53.5 g, 95% pure by HPLC): MP=126.0-126.9° C.;MS (M+1)=291; H¹ NMR (300 MHz): δ (DMSO): 1.97 (2H, pen, J=6.03 Hz),2.55 (2H, t, J=6.03 Hz), 2.88 (2H, t, J=6.03), 6.84 (1H, dd, J=1.88,12.06 Hz) 7.01 (1H, d, J=1.03 Hz), 7.31-7.44 (3H, m), 7.52-7.59 (1H,dd/d, J=6.03, 6.41 Hz).

Step 28-Fluoro-6-(3-fluoro-phenylsulfanyl)-3,4-dihydro-naphthalene-1-carboxylicacid amide

8-Fluoro-6-(3-fluoro-phenylsulfanyl)-3,4-dihydro-2H-naphthalene-1-one(50 g, 0.17 moles) was dissolved in toluene (100 mL) and the resultingmixture was azeotropically distilled under vacuum at 50 to 55° C. untilabout 50 ml of toluene was removed. The resulting suspension was cooledto 25° C. and AlCl₃ (1 g, 2.0% w/w) was added. TMSCN (96%, 24 mL, 0.17moles) was then added at a rate such that the reaction temperature waskept between 20 and 50° C. The reaction was monitored for formation of8-fluoro-6-(3-fluoro-phenylsulfanyl)-3,4-dihydro-naphthalene-1-carbonitrile(which was not isolated) by TLC (Hexanes/EtOAc 4:1). Once complete thereaction was cooled to 5° C. and sulfuric acid (25 mL) was added slowly,maintaining the internal temperature below 30° C. The reaction mixturewas stirred and monitored by TLC (Hexanes/EtOAc 4:1). Once complete thereaction was diluted with acetic acid (250 mL), sulfuric acid (100 mL)and water (25 mL). The reaction mixture was heated to 105° C. to distlloff volatiles. The reaction temperature was maintained at 100 to 105° C.while monitoring the reaction by HPLC. Once complete the reaction wascooled to 40° C. and quenched with water (500 mL) over one hour at 40 to45° C. The reaction mixture was cooled to 20° C., filtered in a glassfilter funnel and washed thoroughly with water, triturated from EtOAc(500 mL) under reflux for one hour, then slowly cooled to 20° C.,filtered in a glass filter funnel, and rinsed with EtOAc. The productwas transferred to a drying vacuum oven, and dried at 45° C. undervacuum with nit rogen purge until a constant weight to afford8-fluoro-6-(3-fluoro-phenylsulfanyl)-3,4-dihydro-naphthalene-1-carboxylicacid amide as a yellow solid (43.1 g), 79% yield, 99% pure by HPLC:MP=212.9-213.7° C.; MS (M+1)=318; H¹ NMR (300 MHz): δ (DMSO): 2.25 (2H,m, J=7.91/7.16 Hz), 2.68 (2H, t, J=7.16/7.91 Hz), 6.52 (1H, t, J=4.7Hz), 7.01 (1H, dd, J=1.51,10.55 Hz), 7.11 (1H, bs, NH) 7.14-7.23 (4H,m), 7.4-7.49 (1H, m), 7.57 (1H, bs, NH).

Step 3[(R)-8-Fluoro-6-(3-fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylaminephosphoric acid salt

To a degassed solution of8-fluoro-6-(3-fluorophenysulfanyl)-3.4-dihydronaphthalene-1-carboxamide(42-g) in tetrahydrofuran (420-ml) was added a degassed solution of[Ru(OAc)₂((S)-MeOBIPHEP)] (120 mg) in tetrahydrofuran (50 ml). Thereaction mixture was subjected to hydrogen gas at 40° C. and 150 psi(10.3 bar) for 20 hours. The reaction was monitored by HPLC forcompletion of the hydrogenation of the olefin. Solvent was removed underreduced pressure from the intermediate solution of(R)-8-fluoro-6-(3-fluorophenysulfanyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylicacid amide (not isolated), and the remaining liquid was treated withBH₃-THF (1 molar solution in THF, 660 ml). The reactor was sealed andheated to 60° C. and stirred for 36 hours. The reaction mixture wasquenched into 10% aqueous sulfuric acid (650 ml) at 5° C. The pH of thesolution was adjusted with 28% aqueous ammonium hydroxide to 9.4 and thebiphasic layers were separated. The organic layer was reduced in volumeto about 600 ml, treated with phosphoric acid (18.3 g) and isopropanol(60 ml). The remaining tetrahydrofuran was atmospherically distilled andreplaced with isopropanol. The solution was cooled to 5° C. and theresulting slurry was aged and filtered. The product was dried at 60° C.under vacuum with a nitrogen purge to afford 50 g of[(R)-8-fluoro-6-(3-fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylaminephosphoric acid salt (94% yield, 100% pure by HPLC): MP=197.5-199.2° C.;MS (M+1)=306; H¹ NMR (300 MHz): δ (DMSO): 1.58-1.85 (3H, m), 2.05-2.16(1H, m), 2.58-2.78 (2H, m), 2.8 (1H, dd, J=12.43 Hz) 2.94 (1H, dd,J=3.77, 12.81 Hz), 3.21-3.31 (1H, m), 6.90 (1H, dd, J=1.51, 10.17 Hz),6.97 (1H, s), 7.06-7.17 (3H, m), 7.36-7.44 (1H, m), 7.92 (5H, bs,NH/H₃PO₄); [α]_(D)=20.9° (MeOH).

Step 4[(R)-8-Fluoro-6-(3-fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-urea

(R)-8-Fluoro-6-(3-fluorophenylsulfanyl)-1,2,3,4-tetrahydronaphthalen-1-yl-methylaminephosphate salt was treated with urea (27.5 g) in anhydrousN-methylpyrrolidinone (140 ml) at 100° C. for 18 hours. The reaction wascooled to 70° C. and water (360 ml) was added dropwise while allowingthe temperature to decline to to room temperature. The resulting solidswere collected and washed with water. The crude filter cake (46 g) wasrecrystallized from toluene (160 ml) and n-heptane (60 ml) to afford[(R)-8-fluoro-6-(3-fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-urea(37.27 g) in 93.8% yield, 99.8% pure by HPLC: MP=130.7-132.4° C.; MS(M+1)=349; H¹ NMR (300 MHz): δ (DMSO): 1.49-1.99 (4H, m), 2.57-2.83 (2H,dt/m), 3.99-3.27 (3H, m), 5.43 (2H, bs, NH), 6.20 (1H, bt, J=6.03),6.96-7.04 (2H, m), 7.1-7.17 (3H, m), 7.37-7.47 (1H, m); [α]_(D)=24.2°(MeOH).

Step 5[(R)-8-Fluoro-6-(3-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-urea

(R)-8-Fluoro-6-(3-fluorophenylsulfanyl)-1,2,3,4-tetrahydronaphthalen-1-ylmethylurea(36-g) in dichloromethane was treated with formic acid (11.9 g) and 30%aqueous hydrogen peroxide with stirring for 18 hours. The reactionmixture was diluted with methylene chloride (1 liter) and water (200 ml)to dissolve the resulting solids. The layers were separated and theorganic layer was sequentially washed with saturated aqueous sodiumbicarbonate (200 ml), water (three times with 200 ml) until the organiclayer was free of peroxide. The methylene chloride layer was filteredand distilled to a minimum volume and the resulting solids werecollected. The crude product was recrystallized from methanol (720ml),filtered, and dried in a vacuum oven at 50° C. to afford[(R)-8-fluoro-6-(3-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-urea(37 g) in 95% yield), 99.7% and 99.8% chiral by HPLC: MP=193.5-194.4°C.; MS (M+1)=381; H¹ NMR (300 MHz): δ (DMSO): 1.46-1.96 (4H, m),2.66-2.80 (1H, ddd, J=6.40, 10.55 Hz), 2.84-2.96 (1H,dt) 3.00-3.22 (3H,m) 5.40 (2H, bs, NH₂), 6.20 (1H, bt, J=6.40 Hz, NH) 7.57 (1H, dd,J=1.13, 8.29 Hz), 7.62 (1H, s/m), 7.64-7.74 (2H, ddd, J=5.27, 5.65, 8.29Hz), 7.83-7.93 (2H, ddt, J=1.88, 2.26, 7.54, 8.29 Hz);[α]_(D)=25.7°(MeOH). Chiral Assay (Area Norm): Column: Chiralpak IA(150×4.6 mm), mobile phase ethanol(isocratic) Flow rate 0.7 ml/min, 25°C., uv @247 nm.: (R)-isomer 99.94/(S)-isomer 0.06.

Example 4 Chiral Catalyst Comparison: (R)- and(S)-6-(3-Fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalene-1-carboxylicacid amide

The synthetic procedure used in this Example is outlined in Scheme F.

In a glove box (O₂ content ≦2 ppm) a 6 ml autoclave equipped with aglass insert and a magnetic stirring bar was charged with 50 mg (0.167mmol) of6-(3-fluoro-phenylsulfanyl)-3,4-dihydro-naphthalene-1-carboxylic acidamide, 6.45 mg (0.00668 mmol) of[Ru(trifluoroacetate)₂((S)-pTol-MeOBIPHEP)] (S/C 25) and 1 ml ofmethanol. The asymmetric hydrogenation was run for 19.5 hours at 40° C.under 40 bar of hydrogen. After cooling to room temperature the pressurewas released from the autoclave, the methanol solution was filteredthrough a silicagel pad and evaporated in vacuo to give(R)-6-(3-fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalene-1-carboxylicacid amide in quantitative yield and with an enantiomeric ratio of 99:1.The conversion was >=99.9%.

The enantiomeric ratio was determined by HPLC using a Chiralcel-AS-Hcolumn, 25 cm*4.6 mm. Eluents: 40% n-heptane, 50% ethanol, 10% heptanewith 0.1% diethyl amine. Flow: 1 ml/min, 40° C., 1 μl. Injection volume:210 nm. Retention times:(R)-6-(3-fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalene-1-carboxylicacid amide 7.3 min,6-(3-Fluoro-phenylsulfanyl)-3,4-dihydro-naphthalene-1-carboxylic acidamide 8.3 min,(S)-6-(3-Fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalene-1-carboxylicacid amide 9.7 min.

The above procedure was repeated using different chiral rutheniumcatalysts to produce corresponding (R) and (S) isomers of6-(3-Fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalene-1-carboxylicacid amide. The results are shown in Table 2, together with catalyst,time, % conversion and enantiomeric ratio. Reaction scale was in allexperiments 50 mg, temperature was 40° C. Examples 4.6 to 4.23 have beenrun at S/C 50.

TABLE 2 Time Conversion Ratio Example Catalyst (hours) (%) R:S 4.1[Ru(OAc)₂((R)-iPr-MeOBIPHEP)] 19.5 >99.9  3:97 4.2[RuCl((R,R)-Et-Duphos)(p-cymene)]Cl 19.5 20  67:33 4.3[Ru(OAc)₂((S)-(3,5-iPr,4-MeO)- 19.5 99.8 99:1 MeOBIPHEP)] 4.3Ru(OAc)₂((all-S)-BICP) 19.5 99.7  75:25 4.5[Ru(OAc)₂((S,R)-PPF-P(tBu)₂)]^(a)) 19.5 99.6 95:5 4.6[Ru(OAc)₂((R)-BIPHEMP)] 22.5 100  2:98 4.7[Ru(trifluoroacetate)₂((S)-TriMeOPHEP)] 22.5 100 99:1 4.8[Ru(OAc)₂((R)-(2-Furyl)- 22.5 99.8  3:97 MeOBIPHEP)] 4.9[Ru(OAc)₂((R)-Cy-MeOPHEP)] 22.5 100  2:98 4.10 [Ru(OAc)₂((S)-3,5-tBu-22.5 100 99:1 MeOBIPHEP)] 4.11 [Ru(OAc)₂((S)-3,5-tBu,4-MeO- 22.5 10098:2 MeOBIPHEP)] 4.12 [Ru(OAc)₂((S)-3,5-TMS- 22.5 100 >99:1  MeOBIPHEP)]4.13 [Ru(OAc)₂((S)-3,5-Me,4-MeO- 22.5 100 98:2 MeOBIPHEP)] 4.14[Ru(OAc)₂((S)-3,5-Ipr,4-MeO- 22.5 100 99:1 MeOBIPHEP)] 4.15[Ru(OAc)₂((R)-(2-Furyl)- 22.5 100  8:92 BIPHEMP)] 4.16[RuI((S)-MeOBIPHEP)(p- 22.5 100 99:1 cymene)]Ib) 4.17[RuCl((S)-MeOBIPHEP)- 22.5 100 99:1 (benzene)]Clb) 4.18[Ru(OAc)₂((R)-BITIANP)] 22.5 100  3:97 4.19 [Ru(OAc)₂((R)-BenzoylO- 22.5100  2:98 BIPHEP)] 4.20 [RuCl₂((S)-3,5-Xyl-MeO- 22.5 100 98:2BIPHEP)((S,S)-DPEN)] 4.21 [RuCl₂((S)-3,5-Xyl-MeO- 22.5 100 99:1BIPHEP)((R,R)-DPEN)] 4.22 [RuCl₂((S)-3,5-tBu-MeO- 22.5 100 99:1BIPHEP)((rac)-DPEN)] 4.23 [Ru((S)-(3,5-tBu-MeOBIPHEP) 22.5 100 >99:1 (DMF)₄][BF₄]₂b) ^(a))Prepared in-situ from [Ru(OAc)₂(cyclooctadiene)]and diphosphine. ^(b))Prepared by addition of 2 molar equivalents ofHBF₄ to [Ru(OAc)₂((S)-(3,5-tBu-MeOBIPHEP)] in DMF

The above procedure was used with several chiral ruthenium catalysts,but replacing the methanol solvent with trifluoroethanol. Thetrifluoroethanol results are shown in Table 3.

TABLE 3 Time Conversion Ratio Example Catalyst (hours) (%) R:S 4.24[Ru(trifluoroacetate)₂((S)- 20 >99.9 90:10 pTol-MeOBIPHEP] 4.25[Ru(OAc)₂((R)-iPr- 20 >99.9 38:62 MeOBIPHEP)] 4.26[RuCl((R,R)-Et-Duphos)(p- 20 1.5 — cymene)]Cl 4.27[Ru(OAc)₂((S)-(3,5-iPr,4- 20 99.9 81:19 MeO)-MeOBIPHEP)] 4.28[Ru(OAc)₂((all-S)-BICP)] 20 99.7 32:68 4.29 [Ru(OAc)₂((S,R)-PPF- 20 99.790:10 P(tBu)₂)]^(a)) ^(a))Prepared in-situ from[Ru(OAc)₂(cyclooctadiene)] and diphosphine.

As can be seen from Tables 2 and 3, asymetric reduction in methanolproduced better (more specific) enantioselectivity than thecorresponding reaction in trifluoroethanol.[RuCl((R,R)-Et-Duphos)(p-cymene)]Cl was the poorest catalyst in methanolin terms of yield and enantioselectivity, and was essentiallynon-reactive in trifluoroethanol. [Ru(OAc)₂(iPr-MeOBIPHEP)] and[Ru(OAc)₂(PPF-P(tBu)₂)] provided high enantioselectivity for both (R)and (S) enantiomers.

Example 5 Chiral Catalyst Comparison: (R)- and(S)-6-(3-Fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalene-1-carboxylicacid amide under acidic conditions

In a glove box (O₂ content ≦2 ppm) a catalyst solution was prepared inthe glass insert of a 6 ml autoclave by reacting a solution of 6.45 mg(0.00668 mmol) of [Ru(trifluoroacetate)₂((S)-pTol-MeOBIPHEP)] (S/C 25)in 0.5 ml of methanol with 0.5 ml of methanol containing 0.020 mmol ofHCl and stirring for 2 h at room temperature. After addition of 50 mg(0.167 mmol) of6-(3-Fluoro-phenylsulfanyl)-3,4-dihydro-naphthalene-1-carboxylic acidamide, the asymmetric hydrogenation was run for 18 hours at 40° C. under40 bar of hydrogen. After cooling to room temperature the pressure wasreleased from the autoclave, the methanol solution was filtered througha silicagel pad and evaporated in vacuo to give(R)-6-(3-Fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalene-1-carboxylicacid amide in quantitative yield and with an enantiomeric ratio of98.8:1.2. The conversion was >=99.9%.

The reaction was repeated with other catalysts according to theprocedure above, and the results are shown in Table 4. Reaction scalewas in all experiments 50 mg, temperature was 40° C.

TABLE 4 Time Conversion Ratio Example Catalyst (Hours) (%) R:S 5.1[Ru(OAc)₂((R)-iPr- 18 13 15:85 MeOBIPHEP)] + 3HCl 5.2[Ru(OAc)₂((R,R)-Et- 18 27 63:37 Duphos)] + 3HCl 5.3[Ru(OAc)₂((S)-(3,5-iPr,4- 18 99.6 99:1  MeO)-MeOBIPHEP)] + 3HCl 5.4[Ru(OAc)₂((all-S)-BICP)] + 18 99.8 82:18 3HCl 5.5 [Ru(OAc)₂((S,R)-PPF-18 99.9 99:1  P(tBu)2)]^(a)) + 3HCl ^(a))prepared in-situ from[Ru(OAc)₂(cyclooctadiene)] + diphosphine.

Example 6(R)-6-(3-Fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalene-1-carboxylicacid amide

In a glove box (O₂ content ≦2 ppm) a 35 ml autoclave equipped with aglass insert and a magnetic stirring bar was charged with 250 mg (0.835mmol) of6-(3-Fluoro-phenylsulfanyl)-3,4-dihydro-naphthalene-1-carboxylic acidamide, 4.03 mg (0.00418 mmol) of[Ru(trifluoroacetate)₂((S)-pTol-MeOBIPHEP)] (S/C 200) and 3 ml ofmethanol. The asymmetric hydrogenation was run for 24 h at 40° C. under40 bar of hydrogen. After cooling to room temperature the pressure wasreleased from the autoclave, the methanol solution was evaporated invacuo. The residue was dissolved in 4 ml of dichloromethane and filteredthrough a silicagel pad, which was washed with a total of 6 ml ofdichloromethane. Evaporation of the filtrate and drying (50° C./10mbar/2 hours) afforded 232 mg of(R)-6-(3-Fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalene-1-carboxylicacid amide as a light yellow solid with an enantiomeric ratio of 99:1.The conversion was >=99.9%.

Example 7(R)-6-(3-Fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalene-1-carboxylicacid amide

In a glove box (O₂ content ≦2 ppm) a 35 ml autoclave equipped with aglass insert and a magnetic stirring bar was charged with 0.40 g (1.336mmol) of6-(3-Fluoro-phenylsulfanyl)-3,4-dihydro-naphthalene-1-carboxylic acidamide, 1.29 mg (0.00134 mmol) of[Ru(trifluoroacetate)₂((S)-pTol-MeOBIPHEP)] (S/C 1000) and 4 ml ofmethanol. The asymmetric hydrogenation was run for 24 h at 40° C. under40 bar of hydrogen. After cooling to room temperature the pressure wasreleased from the autoclave, the methanol solution was evaporated invacuo. Isolation as described in example 4 afforded after drying 405 mgof(R)-6-(3-Fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalene-1-carboxylicacid amide as a light yellow solid with an enantiomeric ratio of 99:1.The conversion was >=99.9%.

The reaction was repeated with other catalysts according to theprocedure above, and the results are shown in Table 5. Reaction scalewas in all experiments 0.40 g, temperature was 40° C., hydrogen pressurein examples 7.3, 7.5 was 10 bar.

TABLE 5 Time Conversion Ratio Example Catalyst (Hours) (%) R:S 7.1[Ru(trifluoroacetate)₂((S)- 24 99.9 99:1 pTol-MeOBIPHEP)] 7.2[Ru(OAc)₂((S)-pTol- 24 99.9 99:1 MeOBIPHEP)] 7.3 [Ru(OAc)₂((S)-pTol- 2499.7 99:1 MeOBIPHEP)] 7.4 [Ru(OAc)₂((S)- 24 99.7 99:1 MeOBIPHEP)] 7.5[Ru(OAc)₂((S)- 24 99.7 99:1 MeOBIPHEP)]

Example 8(R)-6-(3-Fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalene-1-carboxylicacid amide

In a glove box (O₂ content ≦2 ppm) a 50 ml autoclave equipped with amechanical stirrer was charged with 4.00 g (13.36 mmol) of6-(3-Fluoro-phenylsulfanyl)-3,4-dihydro-naphthalene-1-carboxylic acidamide, 1.07 mg (0.00134 mmol) of [Ru(OAc)₂((S)-MeOBIPHEP)] (S/C 10000)and 28 ml of methanol. The asymmetric hydrogenation was run for 18 h at40° C. under 9 bar of hydrogen. After cooling to room temperature thepressure was released from the autoclave, the methanol solution wasevaporated in vacuo. Isolation as described in example 4 afforded afterdrying(R)-6-(3-Fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalene-1-carboxylicacid amide in quantitative yield as an off-white solid with anenantiomeric ratio of 99:1. The conversion was >=99.8%.

The reaction was repeated with other catalysts according to theprocedure above, and the results are shown in Table 6. Reaction scale inexperiments 8.1 to 8.4 was 4.00 g, in experiments 8.5 to 8.10 was 2 g.

TABLE 6 T Time Conversion Ratio Example Catalyst ° C. (Hours) (%) R:S8.1 [Ru(OAc)₂((S)-pTol- 40 18 99.7 99:1 MeOBIPHEP)] 8.2[Ru(trifluoroacetate)₂((S)- 40 18 100 99:1 MeOBIPHEP)] 8.3[Ru(OAc)₂((S)-MeOBIPHEP)] + 5HBF₄ 40 18 99.1 99:1 8.4[RuCl((S)-MeOBIPHEP)(p- 40 18 100 98:2 cymene)]Cl 8.5[Ru(OAc)₂((S)-MeOBIPHEP)] 20 19 67 99:1 8.6 [Ru(OAc)₂((S)-MeOBIPHEP)] 603.5 100 98:2 8.7 [Ru(OAc)₂((S)-MeOBIPHEP)] 80 2.5 100 97:3 8.8[Ru(trifluoroacetate)₂((S)- 20 22 87 99:1 MeOBIPHEP)] 8.9[Ru(trifluoroacetate)₂((S)- 60 3.5 100 98:2 MeOBIPHEP)] 8.10[Ru(trifluoroacetate)₂((S)- 80 2 100 97:3 MeOBIPHEP)] 8.11 a)[Ru(OAc)₂((S)-MeOBIPHEP)] 40 20 100 99:1 a) This experiment was run on a20 g scale under 40 bar of hydrogen.

Example 9(R)-6-(3-Fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalene-1-carboxylicacid amide

In a glove box (O₂ content ≦2 ppm) a 35 ml autoclave equipped with aglass insert and a magnetic stirring bar was charged with 0.40 g (1.336mmol) of6-(3-Fluoro-phenylsulfanyl)-3,4-dihydro-naphthalene-1-carboxylic acidamide, 2.36 mg (0.00267 mmol) of [Ru(OAc)₂((S)-MeOBIPHEP)] (S/C 500) and4 ml of ethanol. The asymmetric hydrogenation was run for ca. 16 h at40° C. under 40 bar of hydrogen. After cooling to room temperature thepressure was released from the autoclave, the ethanol solution wasevaporated in vacuo. Isolation as described in example 4 afforded afterdrying(R)-6-(3-Fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalene-1-carboxylicacid amide in virtually quantitative yield as a light yellow solid withan enantiomeric ratio of 99:1. The conversion was >=99.9%.

The reaction was repeated in other solvents according to the procedureabove, and the results are shown in Table 7. Reaction scale was in allexperiments 0.40 g, temperature was 40° C., hydrogen pressure was 40bar.

TABLE 7 Solvent Time Conversion Ratio Example (vol/vol) (hours) (%) R:S9.1 MeOH 16.5 100 99:1 9.2 i-PrOH 16.5 100 98:2 9.3 CH₂Cl₂ 16.5 48 97:39.4 CH2Cl2/MeOH (2/2) 21 100 99:1 9.5 THF/MeOH (2/2) 18.5 100 99:1 9.6THF/toluene (2/2) 18.5 92 98:2

Example 10 Radioligand Binding Studies

This example illustrates in vitro radioligand binding studies ofcompound of formula I.

The binding activity of compounds of this invention in vitro wasdetermined as follows. Duplicate determinations of 5-HT₆ ligand affinitywere made by competing for binding of [³H]LSD in cell membranes derivedfrom HEK293 cells stably expressing recombinant human 5-HT₆ receptor.Duplicate determinations of 5-HT_(2A) ligand affinity were made bycompeting for binding of [³H]Ketanserin(3424444-fluorobenzoyl)piperidinol)ethyl)-2,4(1H,3H)-quinazolinedione)in cell membranes derived from CHO-K1 cells stably expressingrecombinant human 5-HT_(2A) receptor. Membranes were prepared from HEK293 cell lines by the method described by Monsma et al., MolecularPharmacology, Vol. 43 pp. 320-327 (1993), and from CHO-K1 cell lines asdescribed by Bonhaus et al., Br J. Pharmacol. June; 115(4):622-8 (1995).

For estimation of affinity at the 5-HT₆ receptor, all determinationswere made in assay buffer containing 50 mM Tris-HCl, 10 mM MgSO₄, 0.5 mMEDTA, 1 mM ascorbic acid, pH 7.4 at 37° C., in a 250 microliter reactionvolume. For estimation of affinity at the 5-HT_(2A) receptor alldeterminations were made in assay buffer containing 50 mM Tris-HCl, 5 mMascorbic acid, 4 mM CaCl2, pH 7.4 at 32° C., in a 250 microliterreaction volume.

Assay tubes containing [³H] LSD or [³H]Ketanserin (5 nM), competingligand, and membrane were incubated in a shaking water bath for 75 min.at 37° C. (for 5-HT₆) or 60 min. at 32° C. (for 5-HT_(2A)), filteredonto Packard GF-B plates (pre-soaked with 0.3% PEI) using a Packard 96well cell harvester and washed 3 times in ice cold 50 mM Tris-HCl. Bound[³H] LSD or [³H]Ketanserin were determined as radioactive counts perminute using Packard TopCount.

Displacement of [³H]LSD or [³H]Ketanserin from the binding sites wasquantified by fitting concentration-binding data to a 4-parameterlogistic equation:

${binding} = {{basal} + \left( \frac{{B\; \max} - {basal}}{1 + 10^{- {{Hill}{({{\log {\lbrack{ligand}\rbrack}} - {\log \; {IC}_{50}}})}}}} \right)}$

where Hill is the Hill slope, [ligand] is the concentration of competingradioligand and IC₅₀ is the concentration of radioligand producinghalf-maximal specific binding of radioligand. The specific bindingwindow is the difference between the Bmax and the basal parameters.

Using the procedures of this Example, the compounds(R)-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-urea,[(R)-8-Fluoro-6-(3-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-ureaand(R)—N-(6-Benzenesulfonyl-8-fluoro-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-acetamideshowed a pKi for 5-HT6 of 10.0, 9.8 and 9.75 respectively.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

1. A method of producing a compound of formula k1 or k2

wherein: m is 0 or 1; n is from 0 to 3; Ar is: aryl; or heteroaryl, eachof which may be optionally substituted with: halo; C₁₋₆alkyl;C₁₋₆alkoxy; cyano; hydroxy; C₁₋₆alkylsulfonyl; or halo-C₁₋₆alkyl; Y is—O—; —S(O)_(p)— or —N—R^(a) wherein p is from 0 to 2 and R^(a) ishydrogen or C₁₋₆alkyl; and R¹ is: halo; C₁₋₆alkyl; C₁₋₆alkoxy; orhalo-C₁₋₆alkyl; the method comprising: reducing a dihydronapthaleneamide compound of formula i

with hydrogen gas in the presence of a catalyst of formula j1 or j2Ru(Z)₂(L)  j1;Ru(E)(E′)(L)(D)  j2; wherein: D is an optionally chiral diamine; E andE′ are both halo, or E is hydrogen and E′ is BH₄; L is a chiraldiphosphine ligand; and Z is: halo or R^(b)—CO₂ ⁻ (carboxylate) whereinR^(b) is: C₁₋₆alkyl; halo-C₁₋₆alkyl; C₁₋₆alkoxy; aryl optionallysubstituted with halo; or heteroaryl optionally substituted with halo.2. The method of claim 1, wherein m is
 1. 3. The method of claim 1,wherein n is
 0. 4. The method of claim 1, wherein n is
 1. 5. The methodof claim 1, wherein the catalyst is j1.
 6. The method of claim 1,wherein the catalyst is j2.
 7. The method of claim 1, wherein Ar isphenyl optionally substituted with: halo; C₁₋₆alkyl; C₁₋₆alkoxy; cyano;hydroxy; C₁₋₆alkylsulfonyl; or halo-C₁₋₆alkyl.
 8. The method of claim 1,wherein Ar is phenyl optionally substituted with: fluoro; methyl;methoxy; cyano; hydroxy; methanesulfonyl; or trifluoromethyl.
 9. Themethod of claim 1, wherein Ar is phenyl optionally substituted withfluoro.
 10. The method of claim 1, wherein Ar is: heteroaryl selectedfrom: indolyl; pyrrolyl; pyrazolyl; imidazolyl; and benzimidazolyl, eachoptionally substituted with halo.
 11. The method of claim 1, wherein Aris: heteroaryl selected from: indol-3-yl; 5-fluoro-indol-3-yl;pyrrol-3-yl; 1-methyl-pyrrol-3-yl; pyrazol-4-yl; 1-methyl-imidazol-2-yl;and 5-fluoro-benzimidazol-7-yl.
 12. The method of claim 1, wherein Y isS.
 13. The method of claim 1, wherein Z is acetate.
 14. The method ofclaim 1, wherein the chiral diphosphine ligand L is the (R) or(S)-enantiomer of MeOBIPHEP.
 15. The method of claim 1, wherein L is(6,6′-dimethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine).
 16. The methodof claim 1, wherein the catalyst is [Ru(OAc)₂((S)-MeOBIPHEP)] or[Ru(OAc)₂((R)-MeOBIPHEP)].
 17. The method of claim 1, furthercomprising: reducing a compound of formula k1 or k2

to provide a compound of formula m1 or m2

wherein m, n, Y, Ar and R¹ are as recited in claim
 1. 18. The method ofclaim 17, further comprising: reacting a compound of formula m1 or m2

with a reagent of formula nX—R²  n; to form a compound of formula o1 or o2

wherein: X is a leaving group; R² is: —C(O)—R^(c) or —SO₂—R^(c) whereinR^(c) is C₁₋₆alkyl or —NR^(d)R^(e) wherein R^(d) and R^(e) eachindependently is hydrogen or C₁₋₆alkyl; and m, n, Y, Ar and R¹ are asrecited in claim
 15. 19. The method of claim 18, wherein the compound offormula n is urea.
 20. The method of claim 18, wherein the compound offormula n is acetic anhydride.
 21. The method of claim 18, furthercomprising: oxidizing a dihydronaphthalene carbonitrile compound h

to form the compound of formula i

wherein m, n, Y, Ar and R¹ are as recited in claim
 18. 22. The method ofclaim 19, further comprising: treating a compound of formula g

with cyanate, followed by treatment with sulfuric acid, to form thecompound of formula i

wherein m, n, Y, Ar and R¹ are as recited in claim
 19. 23. A method ofproducing a compound of formula z

wherein: n is from 0 to 3; p is from 1 to 3; R¹ is: halo; C₁₋₆alkyl;C₁₋₆alkoxy; or halo-C₁₋₆alkyl; and R³ is: halo; C₁₋₆alkyl; C₁₋₆alkoxy;cyano; hydroxy; C₁₋₆alkylsulfonyl; or halo-C₁₋₆alkyl; the methodcomprising: reducing a compound of formula y

with hydrogen gas in the presence of a catalyst of formula j1 or j2Ru(Z)₂(L)  j1;Ru(E)(E′)(L)(D)  j2; wherein: D is an optionally chiral diamine; E andE′ are both halo, or E is hydrogen and E′ is BH₄; L is a chiraldiphosphine ligand; and Z is: halo or R^(b)—CO₂ ⁻ (carboxylate) whereinR^(b) is: C₁₋₆alkyl; halo-C₁₋₆alkyl; C₁₋₆alkoxy; aryl optionallysubstituted with halo; or heteroaryl optionally substituted with halo.24. The method of claim 23, wherein n is 0 or
 1. 25. The method of claim24, wherein p is 0 or
 1. 26. The method of claim 25, wherein R¹ is:fluoro; methyl; methoxy; cyano; hydroxy; methanesulfonyl; ortrifluoromethyl.
 27. The method of claim 26, wherein R¹ is fluoro. 28.The method of claim 25, wherein R³ is: fluoro; methyl; methoxy; cyano;hydroxy; methanesulfonyl; or trifluoromethyl.
 29. The method of claim28, wherein R³ is fluoro.
 30. The method of claim 23, wherein thecatalyst is j1.
 31. The method of claim 23, wherein the catalyst is j1.32. The method of claim 23, wherein Z is acetate.
 33. The method ofclaim 23, wherein the chiral diphosphine ligand L is the (R) or(S)-enantiomer of MeOBIPHEP.
 34. The method of claim 23, wherein thecatalyst is [Ru(OAc)₂((S)-MeOBIPHEP)] or [Ru(OAc)₂((R)-MeOBIPHEP)]. 35.The method of claim 23, further comprising reducing a compound offormula z

to provide a compound of formula aa

wherein n, p, R¹ and R³ are as recited in claim
 21. 36. The method ofclaim 35, further comprising reacting a compound of formula aa

with a reagent of formula bb

wherein: X is a leaving group; and R^(f) is C₁₋₆alkyl or —NR^(d)R^(e)wherein R^(d) and R^(e) each independently is hydrogen or C₁₋₆alkyl; andto form a compound of formula cc

wherein n, p, R¹ and R³ are as recited in claim
 31. 37. The method ofclaim 36, wherein the compound of formula bb is urea.
 38. The method ofclaim 36, wherein the compound of formula bb is acetic anhydride. 39.The method of claim 36, further comprising oxidizing a compound offormula cc

to form a compound of formula dd

wherein n, p, R′, R³ and R^(f) are as recited in claim
 32. 40. Themethod of claim 39, further comprising oxidizing a dihydronaphthalenecarbonitrile compound x

to form the compound of formula y

wherein n, p, R′, and R³ are as recited in claim
 35. 41. The method ofclaim 40, further comprising reacting a compound of formula w

with trimethylsilsycyanate, to afford the compound of formula x

wherein n, p, R¹ and R² are as recited in claim 36.